LTA4 hydrolase inhibitor pharmaceutical compositions and methods of use

ABSTRACT

The present invention provides compounds of the formula Ar 1  --Q--Ar 2  --Y--R--Z and pharmaceutically acceptable salts thereof wherein Ar 1  and Ar 2  are optionally substituted aryl moieties, Z is an optionally substituted nitrogen-containing moiety which may be an acyclic, cyclic or bicyclic amine or an optionally substituted monocyclic or bicyclic nitrogen-containing heteroaromatic moiety; Q is a linking group capable of linking two aryl groups; R is an alkylene moiety; Y is a linking moiety capable of linking an aryl group to an alkylene moiety and wherein Z is bonded to R through a nitrogen atom. The compounds and pharmaceutical compositions of the present invention are useful in the treatment of inflammatory diseases which are mediated by LTB 4  production, such as psoriasis, ulcerative colitis, IBD and asthma.

This is a CONTINUATION of application Ser. No. 08/321,184, filed on Oct.11, 1994.

FIELD OF THE INVENTION

This invention relates generally to anti-inflammatory compounds andpharmaceutical compositions, and more particularly to anti-inflammatorycompounds and compositions which are capable of inhibiting leukotrieneA₄ hydrolase.

LTA₄ hydrolase is a requisite enzyme in the biosynthetic pathway leadingto LTB₄ formation. LTB₄ is a proinflammatory compound. R. Lewis, et al.,N. Engl. J. Med. 323, 645-655 (1990) have demonstrated that LTB₄ is apotent granulocyte agonist inducing chemotaxis, aggregation,degranulation, adherence and priming of inflammatory cells for inductionby other agonists. Binding of LTB₄ to receptors is stereospecific withtwo distinct classes of binding sites. A. Lin, et al., Prostaglandins28, 837-849 (1984). A high affinity site 4-5×10⁻¹⁰ M! mediateschemotaxis and chemokinesis while lower affinity sites 0.6-5×10⁻⁷ M!stimulate granular secretion and oxidative burst. The LTB₄ receptor isassociated with a GTP-binding protein that regulates affinity andtransduces signals. T. Schepers, et al., J. Biol. Chem. 267, 159-165(1992). Elevated LTB₄ levels have been reported for many diseases. Mostprominently, elevated LTB₄ levels have been correlated to the pathologyof inflammatory bowel disease (IBD) including Crohn's disease andulcerative colitis and in psoriasis. P. Sharon, et al., Gastroent. 86,453-460; K. Lauritsen, et al., Gastroent. 95, 11-17 (1989); S. Brain, etal., Br. J. Pharm., 83, 313-317 (1984). Other properties of LTB₄ whichmay contribute to disease processes are: stimulation of mucus secretion;stimulation of cytokine production; and the ability to actsynergistically with other inflammatory mediators such as prostaglandinsand cysteinyl leukotrienes thereby amplifying the inflammatory process.

B. Samuelsson, et al., J. Biol Chem., 264, 19469-19472 (1989) have shownthat LTB₄ biosynthesis from arachidonic acid involves the action of 2enzymes, 5-lipoxygenase 5-LO! and LTA₄ hydrolase. 5-LO transformsarachidonic acid to 5-HPETE and subsequent formation of LTA4, which isan unstable allylic epoxide intermediate which is enzymaticallyhydrolyzed by LTA₄ hydrolase to form the dihydroxy acid LTB₄.

LTA₄ hydrolase is distinct from cytosolic and microsomal epoxidehydrolases based on strict substrate requirements, product formation5(S),12(R) vs. 5(S),6(R) for mouse liver cytosolic epoxide hydrolase,and lack of inhibition by inhibitors of cytosolic epoxide hydrolase.LTA₄ hydrolase appears to be ubiquitously distributed in mammaliantissues even in cell types that do not express 5-LO, suggesting theimportance of transcellular metabolism of LTA₄. While peptidomimeticcompounds such as bestatin and captopril have been shown to exhibit LTA4hydrolase inhibitory activity, they are not able to satisfy therequirement of a small organic compound which is capable of cellularpenetration. It would therefore be very advantageous to be able toprovide low molecular weight inhibitors of LTB4 biosynthesis whichpreferably exhibit oral activity in vivo at desirably lowconcentrations.

SUMMARY OF THE INVENTION

Applicants have now discovered that compounds of the formula I

    Ar.sup.1 --Q--Ar.sup.2 --Y--R--Z                           (I)

and pharmaceutically acceptable salts and stereoisomers thereof possessLTA₄ hydrolase inhibitor activity, wherein:

Ar¹ is an aryl moiety selected from the group consisting of:

(i) phenyl, mono-, di-, or tri-substituted phenyl with the substituentsselected from the group consisting of Cl, Br, F, CF₃, lower alkyl, loweralkoxy, NH₂, NO₂ and OH;

(ii) 2-, 4- or 5-thiazolyl,

(iii) 2-, 3- or 4-pyridinyl,

(iv) 2- or 3-thienyl, and

(v) 2- or 3-furyl;

Ar² is an aryl moiety selected from the group consisting of: ##STR1## Qis selected from the group consisting of: (i) --O--,

(ii) --CH₂ --,

(iii) --OCH₂ --,

(iv) --CH₂ O--,

(v) --NH--;

(vi) --NHCH₂ --,

(vii) --CH₂ NH--,

(viii) --CF₂ --,

(ix) --CH═CH--,

(x) --CH₂ CH₂ --, and

(xi) carbon-carbon single bond;

Y is selected from the group consisting of

(i) --O--,

(ii) --S--,

(iii) --NH--,

(iv) --S(O)--, and

(v) --S(O₂)--;

R is selected from the group consisting of:

(i) linear or branched C₂ -C₆ alkylene; or

(ii) C(R¹⁰)(R¹¹)--(CH₂)_(m) ; and

Z is selected from the group consisting of: ##STR2## (vii) a monocyclicor bicyclic heteroaromatic moiety having at least one heteroatom,wherein the heteroatom is nitrogen, and wherein the monocyclicheteroaromatic moiety comprises a 5- or 6-membered ring and the bicyclicheteroaromatic moiety comprises a fused 9- or 10-membered ring;

wherein R¹ and R² are independently selected from the group consistingof:

(i) H,

(ii) lower alkyl or allyl,

(iii) benzyl,

(iv) --(CH₂)_(a) COR¹⁵, ##STR3## (vi) --(CH₂)_(a) --OH R³ and R⁴ areindependently H or lower alkyl;

R⁵ and R⁶ are independently selected from the group consisting of:##STR4## R⁷ is H, halogen, lower alkyl, lower alkoxy, nitro, hydroxy, orR⁷ taken together with R¹⁰ is an alkylene group having one or two carbonatoms;

R⁸ and R⁹ are independently H, halogen, lower alkyl, lower alkoxy, NH₂,NO₂ or OH;

R¹⁰ is H, lower alkyl, or R¹⁰ taken together with R⁷ is an alkylenegroup having one or two carbon atoms;

R¹¹ is H or lower alkyl;

R¹² is selected from the group consisting of:

(i) H,

(ii) --OH or ═O,

(iii) --(CH₂)_(a) COR¹⁵,

(iv) --(CH₂)_(a) CONH(CH₂)_(b) CO₂ R¹⁶,

(v) --NHR¹⁷ ;

R¹³ and R¹⁴ are independently hydrogen, --(CH₂)_(a) COR¹⁵, provided thatat least one of R¹³ and R¹⁴ is hydrogen;

R¹⁵ is --OR¹⁶, --NHR¹⁶ or --NHNH₂ ;

R¹⁶ is H, lower alkyl or benzyl;

R¹⁷ is H, lower alkyl, benzyl, --COR¹⁶ or --CONH₂ ;

X¹ is ##STR5## --S--, or --O--, wherein R¹⁸ is H, lower alkyl, --CONH₂,CSNH₂, --COCH₃ or --SO₂ CH₃ ;

a and b are independently integers of from 0 to 5;

m is 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 1 or 2; and

q is 1, 2 or 3;

provided however that where R is C(R¹⁰)(R¹¹)--(CH₂)_(m), and R¹⁰ takentogether with R⁷ forms an alkylene group having one or two carbon atoms,then --Ar² --Y--R is ##STR6## wherein X is --CH-- or --N--, and r is 1or 2, further provided that wherein R¹, R² or both R¹ and R² are--(CH₂)_(a) COR¹⁵, then a is not O.

DETAILED DESCRIPTION OF THE INVENTION

In one of its embodiments, the present invention entails compounds ofthe formula I

    Ar.sup.1 --Q--Ar.sup.2 --Y--R--Z                           (I)

and pharmaceutically acceptable salts and stereoisomers thereof,wherein:

Ar¹ is an aryl moiety selected from the group consisting of:

(i) phenyl, mono-, di-, or tri-substituted phenyl with the substituentsselected from the group consisting of Cl, Br, F, CF₃, lower alkyl, loweralkoxy, NH₂, NO₂ and OH;

(ii) 2-, 4- or 5-thiazolyl,

(iii) 2-, 3- or 4-pyridinyl,

(iv) 2- or 3-thienyl, and

(v) 2- or 3-furyl;

Ar² is an aryl moiety selected from the group consisting of: ##STR7## Qis selected from the group consisting of: (i) --O--,

(ii) --CH₂ --,

(iii) --OCH₂ --,

(iv) --CH₂ O --,

(v) --NH--;

(vi) --NHCH₂ --,

(vii) --CH₂ NH--,

(viii) --CF₂ --,

(ix) --CH═CH--,

(x) --CH₂ CH₂ --, and

(xi) carbon-carbon single bond;

Y is selected from the group consisting of

(i) --O--,

(ii) --S--,

(iii) --NH--,

(iv) --S(O)--, and

(v) --S(O₂)--;

R is selected from the group consisting of:

(i) linear or branched C₂ -C₆ alkylene; or

(ii) C(R¹⁰)(R¹¹)--(CH₂)_(m) ; and

Z is selected from the group consisting of: ##STR8## (vii) a monocyclicor bicyclic heteroaromatic moiety having at least one heteroatom,wherein the heteroatom is nitrogen, and wherein the monocyclicheteroaromatic moiety comprises a 5- or 6-membered ring and the bicyclicheteroaromatic moiety comprises a fused 9- or 10-membered ring;

wherein R¹ and R² are independently selected from the group consistingof:

(i) H,

(ii) lower alkyl or allyl,

(iii) benzyl,

(iv) --(CH₂)_(a) COR¹⁵, ##STR9## (vi) --(CH₂)_(a) OH R³ and R⁴ areindependently H or lower alkyl;

R⁵ and R⁶ are independently selected from the group consisting of:##STR10## R⁷ is H, halogen, lower alkyl, lower alkoxy, nitro, hydroxy,or R⁷ taken together with R¹⁰ is an alkylenyl group having one or twocarbon atoms;

R⁸ and R⁹ are independently H, halogen, lower alkyl, lower alkoxy, NH₂,NO₂ or OH;

R¹⁰ is H, lower alkyl, or R¹⁰ taken together with R⁷ is an alkylenylgroup having one or two carbon atoms;

R¹¹ is H or lower alkyl;

R¹² is selected from the group consisting of:

(i) H,

(ii) --OH or ═O,

(iii) --(CH₂)_(a) COR¹⁵,

(iv) --(CH₂)_(a) CONH(CH₂)_(b) CO₂ R¹⁶,

(v) --NHR¹⁷ ;

R¹³ and R¹⁴ are independently hydrogen, --(CH₂)_(a) COR¹⁵, provided thatat least one of R¹³ and R¹⁴ is hydrogen;

R¹⁵ is --OR¹⁶, --NHR¹⁶ or --NHNH₂ ;

R¹⁶ is H, lower alkyl or benzyl;

R¹⁷ is H, lower alkyl, benzyl, --COR¹⁶ or --CONH₂ ;

X is ##STR11## --S--, or --O--, wherein R¹⁸ is H, lower alkyl, --CONH₂,CSNH₂, --COCH₃ or --SO₂ CH₃ ;

a and b are independently integers of from 0 to 5;

m is 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 1 or 2; and

q is 1, 2 or 3;

provided however that where R is C(R¹⁰)(R¹¹)--(CH₂)_(m), and R¹⁰ takentogether with R⁷ forms an alkylenyl group having one or two carbonatoms, then --Ar² --Y--R-- is ##STR12## wherein X is --CH-- or --N--,and r is 1 or 2, further provided that wherein Z is ##STR13## and R¹and/or R² is --(CH₂)_(a) COR¹⁵, then a is not O.

In one of its embodiments the present invention entails compounds offormula I Ar¹ --Q--Ar² --Y--R--Z, wherein Z is an amine moiety of theformula ##STR14##

In another of its embodiments the present invention includes compoundsof formula I Ar¹ --Q--Ar² --Y--R--Z, wherein Z is ##STR15## wherein R³,R⁴, R⁵ and R⁶ are defined as set forth hereinbefore.

In another of its embodiments the present invention entails compounds ofthe formula Ar¹ --Q--Ar² --Y--R--Z wherein when Ar¹ --Q--Ar² --Y is##STR16## then (A) R¹ and R² are not simultaneously H or lower alkyl; or(B) R³, R⁴, R⁵ and R⁶ are not simultaneously H.

The compounds of the present invention, in several embodiments, maycomprise a carboxylic acid or ester moiety. It will be appreciated bythe art-skilled that a compound of the present invention comprising anester moiety is readily converted, in vivo, especially when administeredorally, into its corresponding carboxylic acid form. Theester-containing compounds of the present invention are thereforeprodrugs of their carboxylic acid form.

In another of its embodiments the present invention concerns compoundsof formula I Ar¹ --Q--Ar² --Y--R--Z, wherein Z is a monocyclic orbicyclic heteroaromatic moiety having at least one heteroatom, the atleast one heteroatom being nitrogen, wherein the monocyclicheteroaromatic moiety comprises a 5- or 6-membered ring and the bicyclicheteroaromatic moiety comprises a fused 9- or 10-membered ring.

In another of its aspects the invention entails pharmaceuticalcomposition comprising a pharmacologically effective amount of acompound of formula I and a pharmaceutically acceptable carrier.

In still another of its embodiments the present invention involves amethod for treating a mammal exhibiting an LTB4 mediated inflammatorycondition comprising administering to the mammal a pharmacologicallyeffective amount of a compound of formula I.

The term "lower alkyl" means straight or branched chain alkyl having 1to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyland the branched chain isomers thereof.

The term "lower alkoxy" means straight or branched chain alkoxy having 1to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, pentoxy,hexoxy and the branched chain isomers thereof.

The term "allyl" as used herein means the 1-propenyl radical, --CH₂--CH₂ ═CH₂.

The term "halo" means fluoro, cloro, bromo, or iodo.

The phrase "monocyclic or bicyclic heteroaromatic moiety" having atleast one heteroatom which is nitrogen, includes but is not limited toimidazole, triazole, benzimidazole, imidazopyridine, triazolopyridine,thiazole, purine and the like. Such monocyclic and bicyclicheteroaromatic moieties having at least two nitrogen atoms may bebonded, in a compound of the present invention, through any of thenitrogen atoms, as will be appreciated by the person of ordinary skillin the art, to provide two or more conformational isomers.

Such monocyclic heteroaromatic and bicyclic heteroaromatic compounds areincluded in the group of compounds referred to herein as "ZH", whichgroup also includes non-aromatic compounds. Non-aromatic compounds whichare contemplated by reference to "ZH" include acyclic amines, monocyclicamines, and bicyclic amines as defined herein. A compound of formula I,which comprises a "Z moiety" may be readily formed by reacting acompound of the formula Ar¹ --Q--Ar² --R--Cl or Ar¹ --Q--Ar² --R--OTswith an amine or heteroaromatic compound, ZH.

Included within the classes and subclasses of compounds embraced byFormula I are isomeric forms of the described compounds includingdiastereoisomers, enantiomers and tautomeric forms of the describedcompounds. Pharmaceutically acceptable salts of such compounds are alsoincluded as well as pharmaceutically acceptable salts of such isomersand tautomers.

In the structures herein a bond drawn across a bond in a ring indicatesthat the bond can be to any available atom of the ring structure.

The expression "pharmaceutically acceptable salts" is intended toinclude those salts capable of being formed with the compounds of thepresent invention without materially altering the chemical structure orpharmacological properties thereof. Such salts include inorganic andorganic cations or acid addition salts, such as sodium, potassium,calcium, ammonium, alkylammonium, quaternary ammonium, triethanolamine,lysine, hydrochloride, hydrobromide, etc. well known to those skilled inthe art. The foregoing salts are prepared in the conventional manner byneutralization of the compounds of formula I with the desired base oracid.

The compounds of the present invention can be administered to a patientin such oral dosage forms as tablets, capsules, pills, powders,granules, elixirs or syrups, as well as aerosols for inhalation.Likewise, administration may be effected intravascularly,subcutaneously, or intramuscularly using dosage forms known to those ofordinary skill in the pharmaceutical arts. In general, the preferredform of administration is oral. An effective but non-toxic amount of thecompound is employed in treatment. The dosage regimen utilizing thepresent compounds is selected in accordance with a variety of factorsincluding the type, age, weight, sex and medical condition of thepatient; the severity of the condition to be ameliorated; and the routeof administration. A physician of ordinary skill can readily determineand prescribe a "pharmaceutically effective amount" of a compound ofFormula I, that is, the effective amount of the compound required toprevent, treat or arrest the progress of the condition. Dosages of thecompounds of the present invention will range generally between 0.1mg/kg/day to about 100 mg/kg/day and preferably between about 0.5mg/kg/day to about 50 mg/kg/day when administered to patients sufferingfrom allergic or hypersensitivity reactions or inflammation. Thecompounds may also be administered transdermally or topically to treatproliferative skin conditions such as psoriasis. The daily dosage may beadministered in a single dose or in equal divided doses three to fourtimes daily.

As used herein the phrase "LTA₄ hydrolase inhibitor" means a compoundwhich is capable of exhibiting an IC₅₀ of less than 1 mM in an in vitroassay employing 10 μg/ml of LTA₄ hydrolase enzyme (specific activity 600nMoles LTB₄ /min/mg of enzyme) in the presence of 25 μM substrate (LTA₄)in a total reaction volume of 100 μl.

In the pharmaceutical compositions and methods of the present invention,at least one of the active compounds of formula I or a pharmaceuticallyacceptable salt thereof will typically be administered in admixture withsuitable pharmaceutical diluents, excipients or carriers (collectivelyreferred to herein as "carrier" materials) suitably selected withrespect to the intended form of administration, that is, oral tablets,capsules, elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices. For instance, for oral administration in theform of tablets or capsules, the active drug component may be combinedwith any oral non-toxic pharmaceutically acceptable inert carrier suchas lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, mannitol and the like; for oraladministration in liquid form, the active drug component may be combinedwith any oral non-toxic pharmaceutically acceptable inert carrier suchas ethanol and the like. Moreover, when desired or necessary, suitablebinders, lubricants, disintigrating agents and coloring agents can alsobe incorporated in the mixture. Suitable binders include starch,gelatin, natural sugars, corn sweeteners, natural and synthetic gumssuch as acacia, sodium alginate, carboxymethylcellulose, polyethyleneglycol and waxes. Lubricants for use in these dosage forms include boricacid, sodium benzoate, sodium acetate, sodium chloride and the like.Disintigrators include, without limitation, starch, methylcellulose,agar, bentonite, guar gum and the like.

By virtue of their activity as LTA₄ hydrolase inhibitors, the compoundsof Formula I are useful in treating inflammatory conditions mediated byLTB₄ production in mammals such as psoriasis, contact and atropicdermatitis, Crohn's disease, ulcerative colitis, inflammatory boweldisease, multiple sclerosis, ankylosing spondylitis arthritis, asthmaand the like. Similarly, the compounds of Formula I can be used inpreventing recurring inflammatory attacks. A physician or veterinarianof ordinary skill can readily determine whether a subject exhibits theinflammatory condition. A preferred utility relates to treatment ofulcerative colitis.

Among the compounds of the present invention which possess LTA₄hydrolase inhibiting activity are the following:

1- 2-(4-phenoxyphenoxy)ethyl!pyrrolidine;

1- 2-(4-phenylmethyl)phenoxyethyl!pyrrolidine;

1- 2- 4-(2-phenylethenyl)phenoxy!ethyl!pyrrolidine;

1- 2- 4-(4-fluorophenoxy)phenoxy!ethyl!pyrrolidine;

4- 4- 2-(1-pyrrolidinyl)ethoxy!phenyl!methyl!thiazole;

1- 2- 4-(phenylmethoxy)phenoxy!ethyl!pyrrolidine;

4- 4- 2-(1-pyrrolidinyl)ethoxy!phenyl!benzoic acid;

4- 4- 2-(1-pyrrolidinyl)ethoxy!phenoxy!benzoic acid;

5-phenoxy-2- 2-(1-pyrrolidinyl)ethoxy!pyridine;

1- 2- 4-(2-phenylethyl)phenoxy!ethyl!pyrrolidine;

1- 2- 4- (difluoro)phenylmethyl!phenoxy!ethyl!pyrrolidine;

1- 2- 4-(phenylmethyl)phenylthio!ethyl!pyrrolidine, monohydrochloride;

1- 2- 4-(phenylmethyl)phenylsulfinyl!ethyl!pyrrolidine,monohydrochloride;

N- 4- 2-(1-pyrrolidinyl)ethoxy!phenyl!methyl!-3-pyridinamine;

N-(4-phenoxyphenyl)-1-pyrrolidine ethanamine, monohydrochloride;

5-(phenylmethyl)-2- 2-(1-pyrrolidinyl)ethoxy!thiazole;

1- 2- 2-fluoro-4-(phenylmethyl)phenoxy!ethyl!pyrrolidine;

1- 2- 3-fluoro-4-(phenylmethyl)phenoxy!ethyl!pyrrolidine;

1- 2- 2-methyl-4-(phenylmethyl)phenoxy!ethyl!pyrrolidine;

1- 2- 2,6-difluoro-4-(phenylmethyl)phenoxy!ethyl!pyrrolidine;

2- 4- 2-(1-pyrrolidinyl)ethoxy!phenylmethyl!thiazole;

5- 4- 2-(1-pyrrolidinyl)ethoxy!phenyl!methyl!thiazole;

methyl 5-(phenylmethyl)-2- 2-(1-pyrrolidinyl)ethoxy!benzoate;

3- 4- 2-(1-pyrrolidinyl)ethoxy!phenylmethyl!pyridine;

4- 4- 2-(1-pyrrolidinyl)ethoxy!phenylmethyl!pyridine;

1- 2- 4- (3-methoxyphenyl)methyl!phenoxy!ethyl!pyrrolidine;

1- 2- 4- 4-(methoxyphenyl)methyl!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (2-methoxyphenyl)methyl!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (1,3-benzodioxol-5-yl)methyl!phenoxy!ethyl!pyrrolidine;

2- 4- 2-(1-pyrrolidinyl)ethoxy!phenylmethyl!quinoline;

3- 4- 2-(1-pyrrolidinyl)ethoxy!phenylmethyl!quinoline;

1- 2- 4- (2-thiophenyl)methyl!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (3-thiophenyl)methyl!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (2-furanyl)methyl!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (3-furanyl)methyl!phenoxy!ethyl!pyrrolidine;

2- 4- 2-(1-pyrrolidinyl)ethoxy!phenyl!methyl!pyridine;

1- 2- 4- (4-fluorophenyl)methyl!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (4-chlorophenyl)methyl!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (2-fluorophenyl)methyl!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (3-fluorophenyl)methyl!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (3-chlorophenyl)methyl!phenoxy!ethyl!pyrrolidine;

1- 2- 5-(phenylmethyl)pyridin-2-yl!oxy!ethyl!-4-piperidine-carboxamide;

1- 2- 4-(2-naphthalenyl)methoxy!phenoxyethyl!pyrrolidine;

3- 4- 2-(1-pyrrolidinyl)ethoxy!phenoxymethyl!quinoline;

2-methyl-4- 4- 2-(1-pyrrolidinyl)ethoxy!phenoxy!methyl!thiazole;

1- 2- 4- (4-bromophenyl)methoxy!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (2,6-dichlorophenyl)methoxy!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (4-fluorophenyl)methoxy!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (3-chlorophenyl)methoxy!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (2-fluorophenyl)methoxy!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (2-chlorophenyl)methoxy!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (3-trifluoromethyl)phenyl!methoxy!phenoxy!ethyl!-pyrrolidine;

1- 2- 4- (2-methylphenyl)methoxy!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (3-fluorophenyl)methoxy!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (4-methylphenyl)methoxy!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (4-methoxyphenyl)methoxy!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (1-naphthyl)methoxy!phenoxy!ethyl!pyrrolidine;

1- 2- 4- (2-thiophenyl)methoxy!phenoxy!ethyl!pyrrolidine;

methyl-1- 2-4-(phenylmethyl)phenoxy!ethyl!-2S-pyrrolidine-2-carboxylate,monohydrochloride, hydrate;

1- 3- 4-(phenylmethyl)phenoxy!propyl!-4-piperidine-carboxamide;

N- 1- 2- 4-(phenylmethyl)phenoxy)ethyl!pyrrolidin-3-yl!acetamide,monohydrochloride;

phenylmethyl 1- 3- 4-(phenylmethyl)phenoxy!propyl!-L-prolinate;

1- 2- 4- (2-thiophenyl)methyl!phenoxy!ethyl-4-piperidine-carboxamide;

1- 2- 4- (3-thiophenyl)methyl!phenoxy!ethyl!-4-piperidine-carboxamide;

1- 2- 4- (2-thiazolyl)methyl!phenoxy!ethyl!-4-piperidine-carboxamide;

1- 2- 4-(4-methoxyphenyl)methyl!phenoxy!ethyl!-4-piperidine-carboxamide;

1- 2- 4- (4-fluorophenyl)methyl!phenoxy!ethyl!-4-piperidine-carboxamide;

N- 1- 2- 4-(phenylmethyl)phenoxy!ethyl!piperidin-4-yl!acetamide;

N- 2- 4-(phenylmethyl)phenoxy!ethyl!cyclohexanamine, monohydrochloride;

N- 2- 4-(phenylmethyl)phenoxy!ethyl!cyclopentanamine, monohydrochloride;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!piperidine-4-carboxamide;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-3-piperidine-carboxamide;

1- 3- 4-(phenylmethyl)phenoxy!propyl!-3-piperidine-carboxamide;

ethyl-1- 2- 4-(phenylmethyl)phenoxy!ethyl!-4-piperidine-carboxylate,monohydrochloride;

8- 2- 4-(phenylmethyl)phenoxy!ethyl!-1,4-dioxa-8-azaspiro 4.5!-decane,monohydrochloride;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-4-piperidinol, monohydrochloride;

N- 1- 2- 4-(phenylmethyl)phenoxy!ethyl!piperidin-4-yl!-2-benzob!furancarboxamide;

ethyl 3- 1- 2-4-(phenylmethyl)phenoxy!ethyl!piperidine-4-yl!-carbonyl!amino!propanoate;

1- 3-(4-phenoxyphenoxy)propyl!-3-piperidinecarboxamide;

1- 3-(4-phenoxyphenoxy)propyl!-4-piperidinecarboxamide;

1- 2-(4-phenoxyphenoxy)ethyl!-4-piperidinecarboxamide;

1- 2-(4-phenoxyphenoxy)ethyl!-3-piperidinecarboxamide;

ethyl 1- 2-(4-phenoxyphenoxy)ethyl!-4-piperidine-carboxylate,monohydrochloride;

N-methyl-1- 2-(4-phenoxyphenoxy)ethyl!-4-piperidine-carboxamide;

4- 2- 4-(phenylmethyl)phenoxy!ethyl!morpholine, monohydrochloride;

1- 3- 4-(phenylmethyl)phenoxy!propyl!pyrrolidine;

1,1-dimethylethyl 1- 3- 4-(phenylmethyl)phenoxy!propyl!-L-prolinate;

phenylmethyl 3- 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoate;

methyl 4-oxo-1- 3-4-(phenylmethyl)phenoxy!propyl!piperidine-3-carboxylate;

1,1-dimethylethyl 1- 3-4-(phenylmethyl)phenoxy!propyl!piperidine-4-carboxylate;

ethyl N- 3- 4-(phenylmethyl)phenoxy!propyl!glycinate;

ethyl 3- 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoate;

phenylmethyl 3- 2- 4-(phenylmethyl)phenoxy!ethyl!amino!propanoate;

methyl 3- 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoate;

1,1-dimethylethyl 3- 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoate;

ethyl 1- 3- 4-(phenylmethyl)phenoxy!propyl!piperidine-3-carboxylate;

ethyl 1- 2- 4-(phenylmethyl)phenoxy!ethyl!-3-piperidine carboxylate;

ethyl beta- 2-4-(phenylmethyl)phenoxy!ethyl!amino!-3-pyridinepropanoate;

ethyl 3- 4- 4-(phenylmethyl)phenoxy!butylamino!propanoate;

phenylmethyl 3- 4- 4-(phenylmethyl)phenoxy!butyl!amino!-propanoate;

ethyl 3- 5- 4-(phenylmethyl)phenoxy!pentyl!amino!propanoate;

methyl 1- 2- 4-(phenylmethyl)phenoxy!ethyl!-3-pyrrolidineacetate;

methyl 1- 2- 4-(phenylmethyl)phenoxy!ethyl!-3-pyrrolidinecarboxylate;

1- hexahydro-4- 2- 4-(phenylmethyl)phenoxy!ethyl!pyrazin-1-yl!-ethanone,monohydrochloride;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-4-piperidine-carbonitrile,monohydrochloride;

1-2,3-dihydro-5-(phenylmethyl)benzofuran-2-yl!methyl!-4-piperidinecarboxamide;

ethyl 1- 2,3-dihydro-5-(phenylmethyl)benzob!furan-2-yl!methyl!-4-piperidine carboxylate, monohydrochloride;

(+)-1- 2,3-dihydro-2-methyl-5-(phenylmethyl)benzob!furan-2-yl!methyl!pyrrolidine, monohydrochloride;

(+)-1- 2,3-dihydro-3-methyl-5-(phenylmethyl)benzob!furan-2-yl!methyl!-4-piperidinecarboxamide;

2,3-dihydro-5-(phenylmethyl)-2-(1-pyrrolidinylmethyl)furo2,3-b!-pyridine, dihydrochloride;

(+)-1- 5-(phenylmethyl)furo 2,3-b!pyridin-2-yl!methyl!-4-piperidinecarboxamide;

1- 2,3-dihydro-5-phenoxybenzo b!furan-2-yl!methyl!pyrrolidine,monohydrochloride;

1- 2,3-dihydro-5-phenoxybenzob!furan-2-yl!methyl-4-piperidinecarboxamide;

ethyl 1- (2,3-dihydro-5-phenoxybenzob!furan-2-yl)methyl!-4-piperidinecarboxylate, monohydrochloride;

(+)-1-3,4-dihydro-6-(phenylmethyl)-2H-benzopyran-2-yl!methyl!-4-piperidine,monohydrochloride carboxamide;

1- 2,3-dihydro-5-(phenylmethyl)benzob!furan-2-yl!methyl!-N-methyl-4-piperidine carboxamide;

1- (2,3-dihydro-5-phenoxybenzob!furan-2-yl!methyl!-N-methyl-4-piperidinecarboxamide;

2S-alpha-methyl-1- 2-4-(phenylmethyl)phenoxy!ethyl!-4-alpha-pyridinecarboxamide;

N-methyl-1- 2- 4-(phenylmethyl)phenoxy!ethyl!-4-piperidinecarboxamide;

2,3-dihydro-5-(phenylmethyl)benzofuran-2-yl!methyl!-1-pyrazinecarboxamide;

4- 2- 4-(phenylmethyl)phenoxy!ethyl!-4H-imidazo 4,5-b!pyridine;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-1H-imidazo 4,5-b!pyridine;

3- 2- 4-(phenylmethyl)phenoxy!ethyl!-3H-imidazo 4,5-b!pyridine;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-1H-benzimidazole;

5- 2- 4-(phenylmethyl)phenoxy!ethyl!-5H-imidazo 4,5-c!pyridine, hydrate;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-1H-imidazo 4,5-c!pyridine;

3- 2- 4-(phenylmethyl)phenoxy!ethyl!-3H-imidazo 4,5-c!pyridine;

3- 3- 4-(phenylmethyl)phenoxy!propyl!-3H-imidazo 4,5-b!pyridine;

1- 3- 4-(phenylmethyl)phenoxy!propyl!-1H-imidazo 4,5-b!pyridine;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-1H-pyrrolol 3,2-b!pyridine;

1- 3-(4-phenoxyphenoxy)propyl!-1H-benzimidazole;

1- 2-(4-phenoxyphenoxy)ethyl!-1H-benzimidazole;

1- 2- 4-(phenylmethoxy)phenoxy!ethyl!-1H-benzimidazole;

3- 2- 4-(phenylmethoxy)phenoxy!ethyl!-3H-imidazo 4,5-b!pyridine;

1- 2- 4-(phenylmethoxy)phenoxy!ethyl!-1H-imidazo 4,5-b!pyridine;

4- 2- 4-(phenylmethoxy)phenoxy!ethyl!-4H-imidazo 4,5-b!pyridine;

3- 2- 4-(phenylmethoxy)phenoxy!ethyl!-3H-imidazo 4,5-c!pyridine;

1- 2- 4-(phenylmethoxy)phenoxy!ethyl!-1H-imidazo 4,5-c!pyridine;

5- 2- 4-(phenylmethoxy)phenoxy!ethyl!-5H-imidazo 4,5-c!pyridine;

3- 2-(4-phenoxyphenoxy)ethyl!-3H-imidazo 4,5-b!pyridine;

1- 2-(4-phenoxyphenoxy)ethyl!-1H-imidazo 4,5-b!pyridine;

4- 2-(4-phenoxyphenoxy)ethyl!-4H-imidazo 4,5-b!pyridine;

5- 2-(4-phenoxyphenoxy)ethyl!-5H-imidazo 4,5-c!pyridine;

1- 2-(4-phenoxyphenoxy)ethyl!-1H-imidazo 4,5-c!pyridine;

3- 2-(4-phenoxyphenoxy)ethyl!-3H-imidazo 4,5-c!pyridine;

3- 3-(4-phenoxyphenoxy)propyl!-3H-imidazo 4,5-b!pyridine;

1- 3-(4-phenoxyphenoxy)propyl!-1H-imidazo 4,5-b!pyridine;

4- 3-(4-phenoxyphenoxy)propyl!-4H-imidazo 4,5-b!pyridine;

3- 3-(4-phenoxyphenoxy)propyl!-3H-imidazo 4,5-c!pyridine;

1- 3-(4-phenoxyphenoxy)propyl!-1H-imidazo 4,5-c!pyridine;

5- 3-(4-phenoxyphenoxy)propyl!-5H-imidazo 4,5-c!pyridine;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-1H-imidazole, monohydrochloride;

2,3,6,7-tetrahydro-1,3-dimethyl-7- 2-4-(phenylmethyl)phenoxy!ethyl!-1H-purine-2,6-dione;

3- 2- 4-(4-fluorophenoxy)phenoxy!ethyl!-3H-imidazo 4,5-b!pyridine;

1- 2- 4-(4-fluorophenoxy)phenoxy!ethyl!-1H-imidazo 4,5-b!pyridine;

3- 2- 4-(4-fluorophenoxy)phenoxy!ethyl!-3H-imidazo 4,5-c!pyridine;

1- 2- 4-(4-fluorophenoxy)phenoxy!ethyl!-1H-imidazo 4,5-c!pyridine;

5- 2- 4-(4-fluorophenoxy)phenoxy!ethyl!-5H-imidazo 4,5-c!pyridine;

3- 3- 4-(phenylmethyl)phenoxy!propyl!-3H-imidazo 4,5-c!pyridine;

1- 3- 4-(phenylmethyl)phenoxy!propyl!-1H-imidazo 4,5-c!pyridine;

5- 3- 4-(phenylmethyl)phenoxy!propyl!-5H-imidazo 4,5-c!pyridine;

7- 2- 4-(phenylmethyl)phenoxy!ethyl!-7H-purine;

9- 2- 4-(phenylmethyl)phenoxy!ethyl!-9H-purine;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-1H-purine;

3- 2- 4-(phenylmethyl)phenoxy!ethyl!-3H-purine, monohydrochloride;

3- 2,3-dihydro-5-(phenylmethyl)benzo b!furan-2-yl!methyl!-3H-imidazo4,5-b!pyridine, monohydrochloride;

1- 2,3-dihydro-5-(phenylmethyl)benzo b!furan-2-yl!methyl!-1H-imidazo4,5-b!pyridine;

4- 2,3-dihydro-5-(phenylmethyl)benzo b!furan-2-yl!methyl!-4H-imidazo4,5-b!pyridine, hydrochloride;

3- 2,3-dihydro-5-(phenylmethyl)benzob!furan-2-yl!methyl!-3H-1,2,3-triazolo 4,5-b!pyridine;

2- 2,3-dihydro-5-(phenylmethyl)benzob!furan-2-yl!methyl!-2H-1,2,3-triazolo 4,5-b!pyridine;

1- 2,3-dihydro-5-(phenylmethyl)benzob!furan-2-yl!methyl-1H-1,2,3-triazolo 4,5-b!pyridine;

2- 2,3-dihydro-5-(phenylmethyl)benzob!furan-2-yl!methyl!-2H-1,2,3-triazolo 4,5-c!pyridine,monohydrochloride;

1- 2,3-dihydro-5-(phenylmethyl)benzob!furan-2-yl!methyl!-1H-1,2,3-triazolo 4,5-c!pyridine,monohydrochloride;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-1H-benzimidazole-5-amine;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-1H-benzimidazole-6-amine;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-1H-imidazo 4,5-b!pyridinium4-oxide;

3- 2- 4-(phenylmethyl)phenoxy!ethyl!-3H-imidazo 4,5-c!pyridinium,5-oxide;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-1H-imidazo 4,5-c!pyridinium,5-oxide;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-2-pyrrolidine-methanol,monohydrochloride;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-3-pyrrolidinol;

hexahydro-1- 2- 4-(phenylmethyl)phenoxy!ethyl!-1H-azepine,monohydrochloride;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!azocine, monohydrochloride;

2,5-dimethyl-1- 2- 4-(phenylmethyl)phenoxy!ethyl!pyrrolidine,monohydrochloride;

2S-(methoxymethyl)-1- 2- 4-(phenylmethyl)phenoxy!ethyl!pyrrolidine,monohydrochloride;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!piperidine, monohydrochloride;

2,6-dimethyl-1- 2- 4-(phenylmethyl)phenoxy!ethyl!piperidine,monohydrochloride;

1- 2- 4-(phenylmethyl)phenoxy!propyl!piperidine, monohydrochloride;

hexahydro-1- 2- 4-(phenylmethyl)phenoxy!propyl!-1H-azepine,monohydrochloride;

2- 4-(phenylmethyl)phenoxy!butyl!pyrrolidine, monohydrochloride;

2- 4-(phenylmethyl)phenoxy!ethyl!-1- 2-phenylmethyl!pyrrolidine,monohydrochloride;

ethyl beta- 3- 4-(phenylmethyl)phenoxy!propyl!amino!4-pentynoate;

ethyl beta- 2- 4-(phenylmethyl)phenoxy!ethyl!amino!-4-pentynoate;

phenylmethyl 3- 3-4-(phenylmethyl)henoxy!propyl!-(2-propenyl)amino!propanoate;

ethyl 4- 4-(phenylmethyl)phenoxy!butyl!(2-propenyl)amino!propanoate;

ethyl 3- methyl- 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoate;

methyl 3- methyl 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoate,hydrate;

ethyl 3- 3-4-(phenylmethyl)phenoxy!propyl!(pyridin-3-ylmethyl)amino!propanoate;

ethyl methyl 4- 4-(phenylmethyl)phenoxy!butyl!amino!propanoate,triethylamine salt;

1,1-dimethyl-3- 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanol;

phenylmethyl 2,2-dimethyl-3- methyl 3-4-(phenylmethyl)phenoxy!propyl!amino!propanoate;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-4-piperidine-carboxylic acidhydrazide;

N- 2-(aminocarbonyl)ethyl!-1- 2-4-(phenylmethyl)phenoxy!ethyl!-4-piperidinecarboxamide;

N-methyl-3- 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanamide;

3- 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanamide;

1-(4-morpholinyl)-3- 3-4-(phenylmethyl)phenoxy!propyl!amino!-1-propanone;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-3-pyrrolidinecarboxamide;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-3-pyrrolidineacetamide;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-2S-pyrrolidin-2-yl!methylN-phenylcarbamate;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-4-piperidine-carboxylic acid,monohydrochloride, hydrate;

1- 3- 4-(phenylmethyl)phenoxy!propyl!-2S-pyrrolidine-2-carboxylic acid;

3- 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoic acid;

2-methyl-3- methyl 3- 4-(phenylmethyl!propyl!amino!propanoic acid;

3- 4- 4-(phenylmethyl)phenoxy!butyl!amino!propanoic acid;

3- methyl 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoic acid;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-3-pyrrolidinamine, dihydrochloride;

N- 1- 2- 4-(phenylmethyl)phenoxy!ethyl!pyrrolidin-3-yl!urea;

alpha-chloro-N- 1- 2-4-(phenylmethyl)phenoxy!ethyl!pyrrolidin-3-yl!acetamide,monohydrochloride;

1- 2- 4-(phenylmethyl)phenoxy!ethyl!-4-piperidinamine;

N- 1- 2- 4-(phenylmethyl)phenoxy!ethyl!piperidin-4-yl!urea;

hexahydro-1- 2- 4-(phenylmethyl)phenoxy!ethyl!pyrazine, dihydrochloride;

hexahydro-4- 2- 4-(phenylmethyl)phenoxy!ethyl!-1-pyrazinethioamide;

hexahydro-4- 2- 4-(phenylmethyl)phenoxy!ethyl!-1-pyrazinecarboxamide;

hexahydro-1-methylsulfonyl-4- 2- 4-(phenylmethyl)phenoxy!ethyl!pyrazine;

N- 2-alpha-methyl-1- 2-4-(phenylmethyl)phenoxy!ethyl!piperidin-4-beta-yl!acetamide;

4-hydroxy-cis-2-methyl-1- 2- 4-(phenylmethyl)phenoxy!ethyl!piperidine,monohydrochloride;

2- 4-(phenylmethyl)phenoxy!ethanamine, monohydrochloride;

(±)ethyl 2-methyl-1- 2-4-(phenylmethyl)phenoxy!ethyl!piperidine-4-carboxylate;

phenylmethyl 3- 3-(4-phenoxyphenoxy)propyl!amino!propanoate;

phenylmethyl 3- methyl 3-(4-phenoxyphenoxy)propyl!amino!propanoate;

methyl 8- 2- 4-(phenylmethyl)phenoxy!ethyl!-8-azabicyclo3.2.1!octane-3-carboxylate;

3- 3-(4-phenoxyphenoxy)propyl!amino!propanoic acid;

ethyl 1- 2-(4-phenoxyphenoxy)ethyl!piperidine-4-acetate,monohydrochloride;

ethyl 1- 2-5-(phenylmethyl)thien-2-yl!oxy!ethyl!-piperidine-4-carboxylate;

3- methyl 3-(4-phenoxyphenoxy)propyl!amino!propanoic acid;

phenylmethyl 3- 4-(4-phenoxyphenoxy)butyl!amino!propanoate;

5- 1- 2- 4-(phenylmethyl)phenoxy!ethyl!piperidin-4-yl!-1H-tetrazole;

(cis)-2R,6-dimethyl-1- 2-4-(phenylmethyl)phenoxy!ethyl!piperidine-4-carboxamide;

3- 4-(4-phenoxyphenoxy)butyl!amino!propanoic acid;

ethyl 1- 2- 4-3-fluorophenyl)methyl!phenoxy!ethyl!piperidine-4-carboxylate;

ethyl 1- 2- 4-(2-thienylmethyl)phenoxy!ethyl!piperidine-4-carboxylate;

3- 3- 4- (4-fluorophenyl)methyl!phenoxy!propyl!methylamino!propanoicacid, monohydrochloride;

methyl 3- methyl 3- 4-(2-thienylmethyl)phenoxy!propyl!amino!propanoate;

3- methyl 3- 4-(2-thienylmethyl)phenoxy!propyl!amino!propanoic acid,monohydrochloride;

1- 2-(4-phenoxyphenoxy)ethyl!piperidine-4-carboxylic acid,monohydrochloride;

methyl 3- 3- 4-(4-fluorophenyl)methyl!phenoxy!propyl!methylamino!propanoate;

ethyl 1- 2- 4-(4-fluorophenyl)methyl!phenoxy!ethyl!piperidine-4-carboxylate;

ethyl 1- 2- 4-(3-thienylmethyl)phenoxy!ethyl!piperidine-4-carboxylate;

methyl 3- methyl 3- 4-(3-thienylmethyl)phenoxy!propyl!amino!propanoate;

5- 2-methyl-1- 2-4-(phenylmethyl)phenoxy!ethyl!piperidin-4-yl!-1H-tetrazole, monohydrate;

methyl 3- 3- 4-(4-fluorophenoxy)phenoxy!propyl!methylamino!propanoate;

1- 2- 4- (4-fluorophenyl)methyl!phenoxy!ethyl!piperidine-4-carboxylicacid, monohydrochloride;

1- 2- 4-(3-thienylmethyl)phenoxy!ethyl!piperidine-4-carboxylic acid,monohydrochloride;

3- methyl 3- 4-(3-thienylmethyl)phenoxy!propyl!amino!propanoic acid,monohydrochloride;

ethyl 1- 2- 4-(4-fluorophenoxy)phenoxy!ethyl!piperidine-4-carboxylate,monohydrochloride;

1- 2- 4-(4-fluorophenoxy)phenoxy!ethyl!piperidine-4-carboxylic acid,monohydrochloride;

1- 2- 4- (3-fluorophenyl)methyl!phenoxy!ethyl!-4-carboxylic acid,monohydrochloride;

5-phenylmethyl-2- 2-(1-pyrrolidinyl)ethoxy!pyridine;

methyl(cis)-2R,6-dimethyl-1- 2-4-(phenylmethyl)phenoxy!ethyl!piperidine-4-carboxylate;

ethyl 3- 4- 4-phenoxyphenoxy!butyl!amino!propanoate;

1- 2- 4-(2-thienylmethyl)phenoxy!ethyl!piperidine-4-carboxylic acid,monohydrochloride.

The compounds of the invention are prepared from readily availablestarting materials by any of the following alternate processes in aconventional manner. The following reaction schemes describe methodswhich can be employed for preparing the compounds of formula I,including starting materials, intermediates and reaction conditions. Thefollowing terms, as used herein, have the definitions which are given inthe table below.

DEFINITIONS

    ______________________________________                                        NMMO          N-methylmorpholine-N-oxide                                      Me            methyl                                                          SitBuMe.sub.2 t-butyldimethylsilyl                                            nBuLi         n-butyllithium                                                  THF           tetrahydrofuran                                                 Et.sub.2 O    diethyl ether                                                   EtOH          ethyl alcohol                                                   Pd/C          palladium on carbon                                             TFA           trifluoroacetic acid                                            Et.sub.3 SiH  triethylsilane                                                  TBAF          tetrabutylammonium fluoride                                     DMF           dimethylformamide                                               nBu.sub.4 NBr tetra-n-butylammonium bromide                                   TsCl          tosylchloride or p-toluenesulfonyl                                            chloride                                                        TsO           tosylate or p-toluenesulfonate                                  MeOH          methyl alcohol                                                  AcOH          acetic acid                                                     Bn            benzyl                                                          DEAD          diethylazodicarboxylate                                         Ph.sub.3 P    triphenylphosphine                                              MCPBA         metachloroperbenzoic acid                                       LAH           lithium aluminum hydride                                        TsOH          tosic acid or p-toluenesulfonic acid                            LDA           lithium diisopropylamide                                        DSC           disuccinylcarbonate                                             nBuOH         n-butyl alcohol                                                 TFAA          trifluoroacetic anhydride                                       Me.sub.3 SnN.sub.3                                                                          trimethyl-tin azide                                             TMS           trimethyl silyl                                                 Ac.sub.2 O    acetic anhydride                                                Ac            acetate                                                         EtOAc         ethyl acetate                                                   Hep           heptane                                                         ______________________________________                                    

Preparation of the compounds of formula I may be accomplished via one ormore of the synthetic schemes which are set forth hereinafter.

Schemes 1-4 depict various methods for preparing substituted phenols ofthe formula Ar¹ --Q--Ar² --OH, wherein Ar¹ and Ar² are independentlyphenyl, substituted phenyl, pyridyl or thienyl moieties. ##STR17##

Scheme 1 shows methods for producing compounds of the formula Ar¹ --CH₂--Ar² --OH wherein Ar² is a phenyl moiety. Scheme 1 shows two relatedprecursor compounds (1, 2) which may be employed as a starting material.Compound 1 is an alkylated or silylated derivative of p-bromophenol. Aconvenient starting material 1 is 1-bromo, 4-methoxyphenol (i.e., R ismethyl). On the other hand, compound 1 may be readily provided bysilylation of p-bromophenol with t-butyldiphenylsilyl chloride or othersilylating agents (see, Example 2). In either event, compound 1 may bereacted with tert-butyl lithium in an ethereal solvent at lowtemperature, such as in THF at -78° C., and quenched with anarylaldehyde (Ar¹ CHO) to yield compound 3. Similarly, starting fromcompound 2, a p-methoxybenzaldehyde or a silylated derivative ofp-hydroxybenzaldehyde (see, Example 1) may be employed. Compound 2 maybe reacted with an aryl lithium (Ar¹ Li) or aryl magnesium bromide (Ar¹MgBr) to yield compound 3. Regardless of which route is chosen, compound3 is reduced, e.g., by hydrogenation over palladium on carbon or withtriethylsilane, to provide compound 4. Compound 4 is readily deprotectedusing TBAF in THF (desilylation) or using BBr₃ in methylene chloride at-78° C. (dealkylation) to provide compound 5.

Compounds 5 of the formula Ar¹ --CH₂ --Ar² --OH, wherein Ar¹ is apara-halogen-substituted phenyl moiety, such compounds are preferablyprovided by sodium borohydride reduction of a compound 6 to providecompound 3, followed by hydrogenation as described above to affordcompound 5. ##STR18##

Scheme 2 depicts the preparation of compounds of formula Ar¹ --CH₂ --Ar²--OH wherein --Ar² --OH is a substituted phenol R⁸ (R⁹)PhOH and R⁸ andR⁹ are as defined hereinbefore. In this reaction sequence, thesubstituted phenol 7 is reacted with a suitable aryloyl chloride to givethe intermediate aryloyl ester (not shown) which is heated to atemperature of about 160° C. in the presence of AlCl₃ to promote Friesrearrangement which affords the desired compound 8, having thespecifically substituted Ar² moiety. Compound 8 may be reduced utilizingthe two-step reduction sequence (Scheme 1, steps (c) and (d)) to providecompound 9. ##STR19##

Scheme 3 shows a general method for the preparation of phenols of theformula Ar¹ --O--Ar² --OH wherein Ar¹ is a substituted phenol. Ar¹ maybe any substituted arylphenol which is capable of reacting with4-iodoanisole in an Ullman coupling reaction. See, A. Moroz, et al.,Russ. Chem. Rev. 43, 679 (1974). The Ullman reaction is carried outconventionally in the presence of activated copper or copper iodide at atemperature of about 150° C. to 200° C. A particularly preferredsubstituted phenol for providing compounds of the present inventionhaving a substituted Ar¹ moiety is 4-fluorophenol. ##STR20##

Scheme 4 shows a synthesis for making compounds of the formula Ar¹--O-pyridyl-OH (i.e., Ar² is pyridyl). In the reaction,2-amino-5-bromopyridine is combined with an excess of a suitable phenol(Ar¹ OH) and coupled utilizing the Ullman reaction, essentially asdescribed with reference to Scheme 3, to provide the aminopyridinederivative 10. Compound 10 is diazotized with sodium nitrite/H₂ SO₄ /H₂O and decomposed to afford compound 11. ##STR21##

Scheme 5 shows the preparation of compounds of the general formula Ar¹--Q--Ar² --Y--R--Z (Formula I) from compounds of the formula Ar¹--Q--Ar² --YH (12) (wherein R is ethylene, Y is --O--, --NH-- or --S--,R²⁰ and R²¹ are independently hydrogen or lower alkyl, and wherein Ar¹,Q, Ar², and Z are previously defined). Compounds of the formula Ar¹--Q--Ar² --YH may be made in accordance with Schemes 1-4 or may beobtained commercially, including 4-hydroxydiphenylmethane,4-hydroxybenzophenone, 4-benzyloxyphenol, etc.

A compound of the formula Ar¹ --Q--Ar² --YH (12) may be converted into acompound of the present invention via alkylation with any of a varietyof chloroethylaminoalkyl analogs, wherein the aminoalkyl moiety may becyclic or acyclic. Where Q is carbonyl, the carbonyl moiety of compound13 is reduced to --CH₂ -- as depicted in steps (c) and (d) of Scheme 1to afford compound 14. ##STR22##

Scheme 6 shows a presently preferred method for preparing compounds ofthe formula Ar¹ --Q--Ar² --O--R--Z, wherein R is a linear alkylenemoiety. Scheme 6 depicts alternate reaction pathways for adding analkylene linker moiety, R (as defined in formula I) to the phenolichydroxyl group of compound 15, which alkylene linker terminates in areactive halogen or tosylate group. In the pathway which providescompound 17 wherein R is ethylene (i.e., R provides a 2 carbon linker)compound 15 is reacted with ethylene carbonate in DMF in the presence ofnBu₄ NBr to give compound 16 which is subsequently reacted withtosylchloride in dichloromethane and pyridine to provide compound 17wherein X is --OTs.

Where R is a C₃ -C₆ alkylene moiety, compound 15 is reacted with CH₂Cl--(CH₂)_(m) --CH₂ Br (wherein m is 1-4) in the presence of DMF and NaHto provide compound 17 wherein X is Cl.

Compound 17 is reacted with a nitrogen containing compound of theformula ZH in DMF at 60° in the presence of K₂ CO₃, to give compound 18,wherein Z is an acyclic amine moiety, a monocyclic or bicyclic aminemoiety or a monocyclic or bicyclic heteroaromatic moiety as definedhereinbefore with reference to compounds of Formula I. ##STR23##

Scheme 7 describes a method for making compounds of the Formula Iwherein Ar² is thiophene. The synthesis entails reaction of2-bromothiophene or 2-iodothiophene with a terminally substituted diolof the formula CH₂ OH--(CH₂)_(m) --CH₂ OH wherein m=0-4. Such diolsinclude ethylene glycol, 1,3 propanediol, 1,4 butanediol and 1,5pentanediol and 1,6 hexanediol. The reaction is carried in the presenceof copper (II) oxide in the diol as solvent at 120° C. to affordcompound 19. Compound 19 is lithiated on the thiophene ring with nBuLi(2 equivalents) in THF at -78° C. to produce the corresponding 5-lithioanion of compound which is then quenched with a suitablearylmethylbromide (Ar¹ CH₂ Br), for example, benzylbromide, to affordcompound 20, which may be converted into compound of Formula I viatosylation followed by displacement as described in Scheme 6 (20→21→22).##STR24##

Scheme 8 describes the synthesis of compounds of Formula I wherein--Q--Ar² -- is "--CH₂ O-phenyl-" and Ar¹ may be any of a variety of arylmoieities (see, for example, Table 13). The synthesis starts with acompound of Formula I wherein Ar¹ --Q-- is Ph--CH₂ --O-- (23), anddebenzylates the compound, employing H₂, 4% Pd/C, EtOH, to affordintermediate phenol 24 which is alkylated in the presence of NaH in DMFwith any of a variety of arylmethybromides to afford compound 25.Suitable arylmethylbromides include, but are not limited to thearylmethylbromides enumerated with reference to Scheme 7. ##STR25##

Scheme 9 generally depicts methods for preparing compounds of Formula Iwherein Ar² is a 2,5-disubstituted pyridinyl moiety. Such compounds ofthe present invention may be prepared starting from the acid chloride of2-chloro-5-pyridine-carboxylic acid. The acid chloride 26 is combinedwith a suitable aryl compound (Ar¹) and reacted under Friedel-Craftsacylation conditions to provide the chloropyridinyl containing ketone27, which is reacted with a suitable hydroxyalkylamine of the formulaHO--R--Z, wherein R and Z are as defined hereinbefore, to yield compound28 which is subject to a 2-step reduction (shown in steps (c) and (d) ofScheme 1) to provide compound 29 which is a compound of Formula I.##STR26##

Scheme 10 describes preparation of a variety of compounds of the formulaHO--R--Z 33 wherein R is alkylene and Z is defined hereinbefore. Thesecompounds may be employed in the methods described in Scheme 9, step b.In Scheme 10, a benzyloxyalcohol 30 is converted into the correspondingtosylate 31 by reaction with tosylchloride in the presence of pyridineand methylene chloride at 0° C. which is reacted with a secondary amineof the formula ##STR27## in DMF at 60° C., in the presence of K₂ CO₃ toprovide compound 32. Compound 32 is hydrogenated H₂ /Pd, ethanol! toafford compounds of the formula HO--R--Z (33), wherein R is alkylene,and coupled to compounds of the formula Ar¹ --Q--Ar² --OH (see schemes1-4) in the presence of diethylazodicarboxylate (DEAD) andtriphenylphosphine in THF (O. Mitsunoba, Synthesis, 1, (1981)) toprovide compound 34 which is a compound of Formula I.

In another of its embodiments the present invention entails the compoundof the formula ##STR28## wherein r is 1 or 2, and Ar¹, Q, X and Z are asdefined hereinbefore. In this embodiment of the invention the compoundsare rotationally constrained by fusion of a portion of the linker groupR to the Ar² moiety through a 5- or 6-membered fused ring (i.e.,dihydrobenzofuran or tetrahydrobenzopyran). ##STR29##

With reference to Scheme 11, compound 35 is alkylated in DMF in thepresence of sodium hydride with allylbromide or a 2-methyl substitutedallylbromide to afford the corresponding O-allyl ether (not shown),which is heated to 230° C. in a Claissen rearrangement reaction,followed by oxidative cyclization with metachloroperbenzoic acid (mCPBA)in chloroform to yield the alcohol 36. Alcohol 36 is reacted with tosylchloride in pyridine/methylene chloride mixture at 0° C. to afford thecorresponding tosylate 37, which is then condensed (in DMF in thepresence of potassium carbonate) with a primary or secondary amine, ZH,or an aromatic nitrogen containing heterocycle, ZH, wherein Z is definehereinbefore to afford compound 38 which is a compound of formula I.##STR30##

Scheme 12 shows a method for preparing compounds of the presentinvention from phenols of the formula 35. Phenol 35 can be transformedinto tetrahydrobenzopyran analogs via the following six-step (steps(a)-(f)) procedure. In step (a), the phenol 35 is converted into itscorresponding diethylcarbamate 39 employing diethylcarbamoylchloride,KH, and DMF. In step (b), the diethylcarbamate compound 39 is thenortho-lithiated (sec.butyllithium, Et₂ O, TMEDA) and quenched with DMFto afford aldehyde 40. The aldehyde 40 is reacted with allylmagnesiumbromide in step (c) and the resulting alcohol 41 is reduced anddeprotected in step (d) utilizing sulphur-trioxide/pyridine in THF,followed by addition of lithium aluminum hydride to afford phenol 42,which is substituted with but-3-ene in the position ortho to thephenolic hydroxyl. Phenol 42 is oxidatively cyclized in two steps, viaepoxide 43 utilizing mCPBA in CHCl₂, followed by acid-catalyzed epoxidering opening with tosic acid in CHCl₃ in step (f) to afford thetetrahydrobenzopyran containing alcohol 44. Alcohol 44 may be furtherconverted into compounds of the formula I, via formation of thecorresponding tosylate 45, followed by displacement with compounds ofthe formula ZH, as described in Scheme 6. ##STR31##

Scheme 13 represents an alternative procedure to that shown in Scheme 6for attaching an hydoxyethylene moiety to phenols of the formula Ar¹--Q--Ar² --OH (15). In the methods depicted in Scheme 13, phenol 15 isalkylated with t-butylbromoacetate in THF in the presence of sodiumhydride to yield t-butyl ester 47, which is then reduced with LAH in THFto afford the hydroxyethylene substituted analogs, Ar¹ --Q--Ar² --O--CH₂CH₂ --OH 48.

In an analogous reaction sequence, t-butyl ester 47 may bealpha-alkylated via reaction with LDA in THF at -78° C., followed byquenching with an alkylhalide (R²² X) at -78° C. The resultingalpha-substituted ester 49 is reduced (LAH in THF) to afford compound 50having a branched alkylene moiety.

The synthetic route described in Scheme 13 provides compounds which maybe employed in steps (c) and (d) of Scheme 6 to provide compounds ofFormula I having a linear or branched alkylene moiety. ##STR32##

Scheme 14 describes yet another synthetic pathway utilizing t-butylester 49 as a starting material for the preparation of compounds ofFormula I. Here, the t-butyl ester is deprotected with trifluoroaceticacid in methylene chloride to afford the corresponding acid 51 which isthen coupled to an amine compound of the formula ##STR33## using DSC inpyridine and DMF to yield amide 52. As depicted, R²⁰ and R²¹ areindependently hydrogen or alkyl and optionally the defined amine may bea cyclic amine. Amide 52 may be reduced with lithium aluminum hydride inTHF to give compound 53, provided that neither R²⁰ nor R²¹ is (norcomprises) a functional moiety, such as an amide, ester, nitrile or thelike, which is reactive toward LAH. Compound 53 is a compound of formulaI. ##STR34##

Scheme 15 depicts a preferred method for preparing compounds of FormulaI which comprise sterically hindered amines such as2,6-dimethylpiperidine, 2,5-dimethylpyrrolidine and the like. In thismethod, the sterically hindered amine is acylated withchloroacetylchloride in methylene chloride/pyridine at 0° C. to affordα-chloroamide 54. Alkylation of a phenol of the formula Ar¹ Q--Ar² --OHwith the α-chloroamide 54 DMF,NaH! affords amide 55. Provided that theamide group of compound 55 is the only moiety which is reactive towardLAH, reduction of compound 55 with LAH in THF provides a compound 56which is a compound of Formula I. ##STR35##

Scheme 16 describes yet another method for preparation of compounds ofFormula I in which compound 15 is alkylated with a bromodimethyl acetal(60) in DMF in the presence of NaH to afford acetal 57. Subsequentdeprotection with toluene-4-sulfonic acid in THF/H₂ O affordsintermediate aldehyde 58 which is reductively aminated ETCH, KOH, NaBH₃CN! with an amine of the formula HNR¹ R² to afford compound 59 which isa compound of Formula I. ##STR36##

Scheme 17 shows a preferred method for preparing compounds 63 and 64employing an intermediate chloride 60 as an alternative to using thecorresponding tosylate. Compound 60 is aminated with a 100-fold excessof methylamine in acetonitrile at 60° C.-70° C. to afford secondaryamine 61. While compound 61 is a compound of Formula I, compound 61 maybe further elaborated by reaction with a benzylacrylate ester or amethylacrylate ester to provide compound 62 which is also a compound ofFormula I. Where the ester 62 is a benzyl ester, it may be convertedinto its corresponding acid 63 by hydrogenation (H₂ /Pd/EtOH at 2 psi);and where ester 62 is alkyl ester, it may be converted into itscorresponding acid as the hydrochloride salt 64 via hydrolysis with 6NHCl in THF at 60° C.

Among the preferred compounds of the present invention are those inwhich the nitrogen-containing moiety (i.e., Z, as defined herein)comprises at least one polar moiety, such as a carboxylic acid or estermoiety or a carboxamide, acylhydrazide, alkylamide or alanineamidemoiety or the like. ##STR37##

Scheme 18 illustrates further modification of a compound 65 which isalso referred to herein as a β-alanine-based compound of Formula I.Compound 65, which is representative, is reductively aminated with a C₁-C₄ aldehyde or ketone included but not limited to formaldehyde,acetaldehyde, 1-propanal, acetone, methyl-ethyl ketone and the like toprovide compound 66 which is a compound of Formula I. Compound 66 mayoptionally be converted tertiary alcohol 67 (also a compound of FormulaI) by reaction with methylmagnesium bromide in ether at 0° C. ##STR38##

Scheme 19 illustrates a method for introducing one or two methylsubstitution(s) into the backbone of the β-alanine moiety of compound62. Compound 62 may be sequentially alpha-methylated by reaction withLDA in THF at -78° C. followed by quenching with methyliodide to affordcompound 68 or compound 69.

Schemes 20 and 21 show modification of a compound 70 comprising anester-containing Z group to produce compound 71 or compound 72possessing a variety of polar substitutions.

    __________________________________________________________________________    Scheme 20                                                                      ##STR39##                                                                    __________________________________________________________________________    Exemplified Reactions                                                          ##STR40##                                                                     ##STR41##                                                                     ##STR42##                                                                     ##STR43##                                                                     ##STR44##                                                                     ##STR45##                                                                     ##STR46##                                                                     ##STR47##                                                                    __________________________________________________________________________

Scheme 20 depicts the modification of a compound 70 which comprises anester moiety in which the ester is modified by the addition of anucleophile such as an amine or hydrazine to provide compound 71 asshown in the "Exemplified Reactions" set forth in equations (a)-(h) ofScheme 20.

    ______________________________________                                        Scheme 21                                                                      ##STR48##                                                                     ##STR49##                                                                    ______________________________________                                        Exemplified Reactions                                                          ##STR50##                                                                     ##STR51##                                                                     ##STR52##                                                                     ##STR53##                                                                     ##STR54##                                                                     ##STR55##                                                                    ______________________________________                                    

Scheme 21 shows the conversion of compound 70 which comprises an estermoiety to corresponding acid 72 via one of three reactions: (1) basichydrolysis; (2) acidic hydrolysis, which is preferred where R is a loweralkyl or benzyl; or (3) hydrogenolysis over palladium on carbon in EtOH,which is especially preferred where R is benzyl.

Schemes 22 and 23 show alternative methods for preparing a nitrilecontaining compound 74 which is a compound of Formula I and whichconveniently may be employed as an intermediate in the preparation ofvarious compounds of the present invention described in Scheme 24 below.##STR56##

In Scheme 22 dehydration of a carboxamide containing compound 73 withtrifluoracetic anhydride in pyridine/THF at 0° C. affords thecorresponding nitrile containing compound 74. ##STR57##

Scheme 23 shows a synthetic route to compound 74 which is analogous toScheme 22. In Scheme 23, the t-butoxycarbonyl-protected (i.e.,BOC-protected) piperidine amide 75 is dehydrated using the conditionsdescribed in Scheme 22 (TFAA/pyridine) to afford protected nitrile 76.Deprotection of nitrile 76 with trifluoroacetic acid in methylenechloride at 0° C. affords the corresponding secondary amine 77 which maybe coupled to compound 17 essentially as described in Scheme 6 (step d)to afford nitrile-containing compounds of the present invention, whichmay be utilized as described in Scheme 24. ##STR58##

Scheme 24 shows several reaction pathways which may be used to modifythe nitrile moiety of compound 78 to afford a variety of compounds ofthe present inventions. In step (a) the nitrile moiety of compound 78 iscondensed with hydroxylamine in an alcoholic solvent such as ethanol,propanol, butanol, or the like to afford the correspondinghydroxyamidine 79 which is a compound of the present invention as wellas an intermediate for step (b) of this Scheme. Thus, in step (b),hydroxyamidine 79 may be hydrogenated in ethanol over palladium oncarbon to afford the corresponding amidine 80 which is a compound of thepresent invention. Alternatively, hydroxyamidine 79 may be cyclized withphosgene in toluene at 60° C. to yield 81 which is a compound of thepresent invention. Scheme 21 furthers shows, in step d, reacting nitrile78 with trimethyl-tin azide in xylene at 130° C. to afford thecorresponding tetrazole containing compound 82 which is a compound ofthe present invention. ##STR59##

Scheme 25 illustrates modification of compounds having a cyclic aminemoiety derivatized with an acetamide group (compound 83) to convert theacetamide moiety to a primary amine (HCl/EtOH/H₂ O 80°-100° C.) toprovide compound 84 which, in turn, may be modified to a urea moiety(TMS-NCO) to provide compound 85 or to an alpha-chloroamide moiety toprovide compound 86. Compounds 84, 85 and 86 are compounds of thepresent invention.

Compounds of the present invention containing a piperazine moiety,compound 87, may be derivatized in essentially the same manner asdescribed in Scheme 24 to yield derivatized piperazine compounds whichinclude methylsulfonamide-containing compound 88, thiourea-containingcompound 89 or urea-containing compound 90, as illustrated in Scheme 26.##STR60##

Scheme 27 shows methods for preparing compounds of the invention havinga 4-substituted 2-methyl piperadine moiety. In Scheme 27, di-protected4-piperadol 91 is methylated in the 2-position using the method of P.Beak, et al., J. Org. Chem. 58, 1109 (1993). The 2-methyl derivative 92is deprotected using trifluoracetic acid in methylene chloride at 0° C.to yield the secondary amine 93 which, in turn, is coupled to a compoundof the formula Ar¹ --Q--Ar² --CH₂ CO₂ H (compound 51, wherein R ishydrogen) using the method described in Scheme 14, step (b). Theresulting amide 94 may be reduced and desilylated in one step with LAHin THF at room temperature to afford the trans di-substituted piperadine95 which is a compound of the present invention.

Alternatively, amide 94 may be desilylated (TBAF) to afford alcohol 96which is subjected to a four-step reaction sequence (steps(f)(1)-(f)(4)) to afford cis 2-methyl, 4-amino piperadine 91.

The four-step reaction scheme consists of reacting the alcohol 96 withTsCl in methylene chloride/pyridine at 0° C. to give the correspondingtosylate which is displaced with sodium azide in DMF (60°-80° C.) toafford the corresponding azide having inverted stereochemistry (i.e.,trans→cis). The azide is hydrogenated at atmospheric pressure inmethanol over 4% palladium on carbon to afford the corresponding amineof the formula ##STR61## the amide function of which is reduced with LAHin THF at room temperature to afford compound 91. Optional acylation ofthe 4-amino moiety of compound 97 affords compound 98. ##STR62##

Scheme 28 shows methods for making cis 2-methyl, 4-substitutedpiperidines, 108, (which are compounds encompassed within "ZH" as usedherein) which compounds can be coupled in a coupling reaction asdescribed in Scheme 6 to afford compounds of formula I. Scheme 28 startswith commercially available 2-chloro-6-methylpyridine-4-carbonylchloride (Maybridge Chem.) which is reacted with oneof the following: (1) ammonium hydroxide; (2) methanol; or (3)methylamine. The reactions each may be carried out in methylene chlorideat 0° C. to afford a substituted pyridine of the formula 99 wherein R is(1) NH₂ ; (2) OCH₃ ; or (3) NHCH₃, respectively. Compound 99 ishydrogenated over ruthenium catalyst (e.g. 5% ruthenium on charcoal) at140° C. at 60 psi to afford a cis 2-methyl, 4-substituted piperidine100. ##STR63##

Scheme 29 shows methods for preparing cis 2,6 dimethyl, 4-substitutedpiperidines 103 and 105 (which compounds are also encompassed within"ZH" as defined herein) which may be coupled in a coupling reaction asdescribed in Scheme 6 to afford compounds of the present invention.Scheme 29 starts from 2,6-dimethyl-4-cyanopyridine 101 which is preparedin accordance with the method of Feely, et al., JACS 81, 4004 (1959).Compound 101 is hydrolyzed using basic hydrogen peroxide in ethanol toafford primary amide 102 which, in turn, is hydrogenated under theconditions described in Scheme 28 to afford the correspondingtri-substituted piperidine 103.

Alternatively, primary amide 102 may be esterified using HCl(g) inmethanol to afford the corresponding methylester 104 which, in turn, maybe hydrogenated as described in Scheme 28 to afford the correspondingtri-substituted piperidine 105. ##STR64##

Scheme 30 shows methods for preparing 2-methyl 4-substituted piperidinesand 2,6-dimethyl 4-substituted piperidines 108 which can be coupled asdescribed in Scheme 6 to afford compounds of the present invention. InScheme 30, compound 106 may be prepared by the combination of the methodof R. F. Evans et al., JOC 27, 1665 (1962), followed by the method of R.J. Martins et al., RECUEIL 86, 655 (1967). Compound 106 is acetylatedusing acetic anhydride and pyridine and the resultant acetamide 107 ishydrogenated under the conditions described in Scheme 28 to affordcompound 108. ##STR65##

Scheme 31 shows a method for preparing substituted tropones (referred toherein as "ZH") which tropones may be coupled in accordance with Scheme6 to provide compounds of the present invention. In Scheme 28, tropone109 (which may be derived from commercially available N-methyl tropone)is N-benzylated with benzylbromide in DMF in the presence of K₂ CO₃ at0° C. to provide 110 which is homologated with the lithium anion derivedfrom dimethylsilyldithiane (THF, nBuLi, 0° C.) to give the dithianeadduct 111.

The dithiane adduct 111 is converted into the corresponding methyl esterusing mercuric chloride-catalyzed hydrolysis in methanol to providemethyl ester 112 which is debenzylated via hydrogenation inmethanol/concentrated hydrochloric acid over palladium hydroxide oncarbon at 60 psi to afford carboxymethyl-substituted tropane 113. Itshould be understood that such carboxymethyl-substituted tropanes may befurther modified in accordance with the method described in Schemes 20and 21 to provide a wide variety of substituted tropones. ##STR66##

Scheme 32 shows the preparation of 3-substituted pyrrolidine 119 frommethy-1-benzyl-5-oxo-3-pyrrolidine carboxylate 114 which is commerciallyavailable. In step (a) of Scheme 32 compound 114 is reduced with LAH inTHF at room temperature to afford alcohol 115, which is then reactedwith thionyl chloride at reflux to give to the corresponding chloride116. Compound 116 is then treated with aqueous sodium cyanide at 100° C.for about 48 hours to yield the nitrile 117. Hydrolysis of nitrile 117in methanolic HCl affords methyl ester 118, which may be debenzylatedusing hydrogen-transfer hydrogenation conditions (1,4 cyclohexadiene,methanol 10% Pd/C) to provide the 3-substituted pyrrolidine 119.##STR67##

Scheme 33 shows a 3-step procedure for the preparation of2.2.1!-2-aza-bicycloheptane 123 from 2-(carbobenzyloxy)2-azabicyclo2.2.1!heptan-5-one 120. Compound 120 is prepared as described by F. IvyCarroll, et al., J. Med. Chem. 35, 2184 (1992). Compound 120 iscondensed with methyl(triphenylphosphoranylidene)acetate in THF at50°-70° C. to afford α,β unsaturated ester 121. Reduction of compound121 with magnesium in methanol affords the corresponding saturated ester122. Compound 122 is decarbobenzyloxylated 5% Pd/C, MeOH, aq, HCl! toafford the corresponding amine 123. ##STR68##

Scheme 34 shows the preparation of compounds of the present inventionwhich are characterized as containing a 2-aza 2.2.1!bicyclo heptane or2-aza 2.2.2!bicyclooctane moiety. Tosylate 124 is displaced with sodiumazide in DMF to afford the corresponding azide 125. Azide 125 is reducedwith LAH in THF to afford the corresponding primary amine 126. Primaryamine 126 may be further condensed in an aza Dieis-Alder reaction in thepresence of either cyclopentadiene or 1,3 cyclohexadiene 40% aqueousformaldehyde, in 1N HCl! to afford azabicyclic alkenes 127 which may behydrogenated in ethanol over 4% palladium on carbon at 5 psi to affordcompounds 128. Compounds 126, 127 and 128 are compounds of the presentinvention. ##STR69##

Scheme 35 describes preparation of compounds 133 of the invention havinga 3-aza 3.2.1!bicyclo octane-7-methoxycarbonyl moiety.5-norbornene-2-carboxylate is esterified in DMF containing methyl iodideand potassium carbonate. The resulting methyl ester 130 isdihydroxylated with catalytic osmium tetroxide in acetone/H₂ O usingN-methylmorpholine oxide to recycle the catalyst. The resulting diol 131is cleaved with aqueous sodium periodate in t-butanol to afforddialdehyde 132. Condensation of dialdehyde 132 with amine 126 inmethanol followed by reduction with sodium oyanoborohydride affordscompound 133 which is a compound of the invention.

EXAMPLE 1 ##STR70##

To a stirred solution of 4-hydroxybenzaldehyde (12.3 g, 0.1 mol,Aldrich) in DMF (50 mL) was added t-butyldimethylsilyl chloride (18.1 g,0.12 mol) and imidazole (17 g, 0.25 mol). The mixture was stirred atroom temperature for 16 hours, and diluted with pentane (200 mL). Theorganic layer was washed with water (3×) and brine, dried over Na₂ SO₄and concentrated in vacuo to give 25 g of the title compound as yellowoil. The resulting product had the following properties: ¹ H NMR: 300MHz spectrum consistent with proposed structure.

M⁺ =236.

EXAMPLE 2 ##STR71##

The compound of example 2 was prepared in the same manner as describedin example 1, replacing 4-hydroxybenzaldehyde by 4-bromophenol. Theresulting product had the following properties: ¹ H NMR: 300 MHzspectrum consistent with proposed structure. Analysis Calcd for C₁₂ H₁₉OSiBr 0.4H₂ O: C, 48.94; H, 6.78. Found: C, 48.82; H, 6.73.

M⁺ =287.

EXAMPLE 3 ##STR72##

The title compound was prepared in the same manner as Example 44sustituting 4-hydroxybenzaldehyde. The crude aldehyde waschromatographed (silica gel, methanol/methylene chloride/ammoniumhydroxide 5/94/1) to afford an amber oil. The product had the followingproperties: H.R.M.S. M⁺ calcd for C₁₃ H₁₇ NO₂ : 219.1259. Found219.1239.

EXAMPLE 4 ##STR73##

2-Bromothiophene (815 mg, 5 mmols, Aldrich) was dissolved in dry THF (20mL) and cooled to -78° C. n-Butyllithium (3.4 mL of 1.6M solution) wasadded and the reaction was stirred for 2 hours under Argon. The aldehydeof Example 1 (1.18 g, 5 mmols) in THF (1 mL) was added and reactionmixture allowed to warm to room temperature over 1.5 hours. Water wasadded and the solution was extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with brine, dried over Na₂ SO₄,filtered and concentrated in vacuo. The residue was chromatographed onsilica gel using EtOAc/Hep (20/80) as eluant to give 160 mg of compoundas yellow oil. The resulting product had the following properties: ¹ HNMR: 300 MHz spectrum consistent with proposed structure.

The compounds exemplified in Table 1 were prepared essentially asdescribed in Example 4 above except that 2-bromothiophene was replacedwith the indicated aryl(halide)compound.

                                      TABLE 1                                     __________________________________________________________________________     ##STR74##                                                                    Ex. No.                                                                           Compound                Aryl(halide)Ar.sup.1                                                                     Analysis                               __________________________________________________________________________         ##STR75##              3-bromothiophene                                                                         C.sub.17 H.sub.24 O.sub.2 SSi                                                 Calc: C, 63.70; H, 7.55 Found: C,                                             63.85; H, 7.42                         6                                                                                  ##STR76##              thiazole   C.sub.16 H.sub.23 NO.sub.2 SSi                                                Calc: C, 58.78; H, 7.28; N, 4.28                                              Found: C, 63.85; H, 7.42; N, 4.14      7                                                                                  ##STR77##              4-bromoanisole                                                                           C.sub.20 H.sub.27 O.sub.3 SSi                                                 Calc: C, 69.72; H, 8.19, Found: C,                                            69.55; H, 8.29. M.sup.+  344.          8                                                                                  ##STR78##              Ex 2 + 3- fluorobenzaldehyde                                                             C.sub.19 H.sub.26 FO.sub.2 Si:                                                Calc: C, 68.64; H, 7.58. Found: C,                                            68.39; H, 7.69.                        9                                                                                  ##STR79##              3-fluoro-p-anisaldehyde Arylhalide                                                       Compound was fully characterized                                              in the next step. See Example No.                                             314.                                   __________________________________________________________________________

EXAMPLE 10 ##STR80##

4-Bromoanisole (1.5 g, 8 mmol, Aldrich) was dissolved in dry THF (35 mL)and cooled to -78° C. n-Butyllithium (5 mL of 1.6M solution) was addedand the reaction was stirred for 2 hours under Argon.3-pyridinecarboxaldehyde (856 mg, 8 mmol) in THF (1 mL) was added andreaction mixture allowed to warm to room temperature over 1.5 hours.Water was added and the solution was extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was chromatographedon silica gel using EtOAc/Hep (20/80) as eluant to give 1 g of compoundas white solid. The resulting product had the following properties: ¹ HNMR: 300 MHz spectrum consistent with proposed structure. Analysis calcdfor C₁₃ H₁₃ NO₂ 0.1 H₂ O: C, 71.94; H, 6.13; N, 6.45. Found: C, 72.04;H, 6.19; N, 6.39.

EXAMPLE 11 ##STR81##

The product of example 4 (0.5 mmol) was mixed with Et₃ SiH (0.5 mL,Aldrich) and TFA (0.4 mL) and stirred at room temperature for 6 hoursunder Argon. The reaction mixture was concentrated and the residueobtained was basified with 10% aqueous NaOH solution. The reactionsolution was extracted with ether (3×10 mL). The combined organic layerswere washed with brine, dried (Na₂ SO₄) and filtered. The filtrate wasconcentrated to give 160 mg product. The resulting product was fullycharacterized in the next step. See Example No. 148.

The compounds exemplified in Table 2 were prepared essentially asdescribed in Example 11, above, except that the precursor compounds ofExamples 5-10 were substituted for the compound of Example 4.

                                      TABLE 2                                     __________________________________________________________________________     ##STR82##                                                                    Ex. No.                                                                           Compound                Ar.sup.1 CH(OH)Ar.sup.2 OH                                                              Analysis                                __________________________________________________________________________    12                                                                                 ##STR83##              Ex. 5     Compound was fully characterized in                                           the next step. See Example No.                                                149.                                    13                                                                                 ##STR84##              Ex. 6     C.sub.19 H.sub.23 NOSiS Calc: C,                                              62.90; H, 7.59; N, 4.58 Found: C,                                             62.60; H, 7.76; N, 4.36                 14                                                                                 ##STR85##              Ex. 7     M.sup.+  = 328                          15                                                                                 ##STR86##              Ex. 8     Compound was fully characterized in                                           the next step. See Example No. 22.      16                                                                                 ##STR87##              Ex. 9     Compound was fully characterized in                                           the next step. See Example No.                                                314.                                    17                                                                                 ##STR88##              Ex. 10    M.sup.+  = 199                          __________________________________________________________________________

EXAMPLE 18 ##STR89##

The product of example 11 was treated with tetrabutylammonium fluoride(2.5 mL of 1M solution, Aldrich) and the mixture was stirred at roomtemperature for 2 hours. The solvent was removed under reduced pressure,the residue obtained was treated with water and ether. The organic layerwas separated and washed two times with water and brine, dried over Na₂SO₄ and concentrated in vacuo to give 90 mg of the title compound asyellow oil. The resulting product was fully characterized in the nextstep. See Example No. 148.

The compounds exemplified in Table 3 were prepared essentially asdescribed in Example 18, above, except that the silylated precursorcompounds indicated in Table 3 were substituted for the compound ofExample 11.

                                      TABLE 3                                     __________________________________________________________________________     ##STR90##                                                                    Ex. No.                                                                           Compound             Ar.sup.1 CH.sub.2 Ar.sup.2 OR                                                         Analysis                                     __________________________________________________________________________    19                                                                                 ##STR91##           Ex. 12  Compound was fully characterized in the                                       next step. See Example No. 149.              20                                                                                 ##STR92##           Ex. 13  Compound was fully characterized in the                                       next step. See Example No. 231.              21                                                                                 ##STR93##           Ex. 14  M.sup.+  = 214                               22                                                                                 ##STR94##           Ex. 15  C.sub.13 H.sub.11 OF0.3H.sub.2 O Calc:                                        C, 75.20; H, 5.63. Found: C, 75.37; H,                                        5.61. M.sup.+  = 202                         23                                                                                 ##STR95##           Ex. 16  Compound was fully characterized in the                                       next step. See Example No.                   __________________________________________________________________________                                     314.                                     

EXAMPLE 24 ##STR96##

The product of example 17 (500 mg, 2.5 mmol) was dissolved in CH₂ Cl₂(10 mL) and cooled to -78° C. Boron tribromide (3 mL of 1M solution inCH₂ Cl₂, Aldrich) was added and the reaction mixture allowed to warm toroom temperature over 1 hour. The reaction mixture was continued to stirfor 6 hours. Water was added and the reaction solution was extractedwith CH₂ Cl₂ (30 mL×3). The combined organic layers were washed withbrine, dried over Na₂ SO₄, filtered and concentrated in vacuo. Theresulting product had the following properties: ¹ H NMR: 300 MHzspectrum consistent with proposed structure.

M⁺ =185.

EXAMPLE 25 ##STR97##

4-Fluoro-4'-hydroxybenzophenone (2 g, 9.3 mmol) was dissolved in EtOH(85 mL) and water (17 mL) and cooled to 0° C. Sodium borohydride (1.7 g,46 mmol) was added and the mixture was stirred at room temperature for16 hours. The mixture was treated with 1N NaOH and extracted with ethylacetate. The organic phase was washed with brine, dried over Na₂ SO₄ andconcentrated. The residue was deoxygenated in the same manner asdescribed in example 11. The resulting product had the followingproperties: ¹ H NMR: 300 MHz spectrum consistent with proposedstructure. Analysis calcd for C₁₃ H₁₁ OF 0.1 H₂ O: C, 76.53; H, 5.53.Found: C, 76.49; H, 5.46.

M⁺ =202.

EXAMPLE 26 ##STR98##

To a solution of 4-methoxyphenylacetic acid (3.32 g, 20 mmol) in benzene(30 mL) was added oxalyl chloride (2.0 mL, 23 mmol) followed by 1 dropof DMF. The mixture was stirred at 25° C. for 1.5 h and concentrated. Toa solution of the crude acid chloride in ether (50 mL) at 0° C. wasadded ethereal diazomethane until N₂ evolution ceased. HBr gas wasbubbled through the solution at 0° C. for 30 min (until N₂ no longerevolved). The solution was washed with water, dilute NaHCO₃ and brineand the ether layer dried over Na₂ SO₄ and concentrated to provide abrown oil which was used without further purification.

EXAMPLE 27 ##STR99##

A solution of thioformamide in dioxane was prepared by refluxingformamide (1.5 mL, 43 mmol) and P₂ S₅ (3.3 g, 7.3 mmol) in 70 mL dioxanefor 2 h. The solution was added to a solution of the product fromExample 26 (1.0 g, 4.1 mmol) and 2 g MgCO₃ in 10 mL dioxane and themixture refluxed for 1 h. The mixture was cooled and poured into etherand 1N NaOH. The ether layer was separated and was washed with brine,dried over Na₂ SO₄ and concentrated. Flash chromatography using agradient of 10:1 to 5:1 hexane/EtOAc provided the title compound as acolorless oil.

EXAMPLE 28 ##STR100##

To a solution of the product from Example 27 (0.52 g, 2.53 mmol) in CH₂Cl₂ (10 mL) at -78° C. was added 8 mL of 1N BBr₃ in CH₂ Cl₂ and themixture stirred at -8° C. for 20 min and at 25° C. for 16 h. The mixturewas poured into H₂ O and the CH₂ Cl₂ was separated, washed with brine,dried over Na₂ SO₄ and concentrated to provide the product as a boronicacid complex. The product was dissolved in methanol and treated withconcentrated HCl. After stirring at 25° C. for 25 h, the mixture wasconcentrated to give the title compound as an oil.

EXAMPLE 29 ##STR101##

The compound of example 29 was prepared in the same manner as describedin example 25, replacing 4-fluoro-4'-hydroxybenzophenone with4-chloro-4'-hydroxybenzophenone. The resulting product had the followingproperties: ¹ H NMR: 300 MHz spectrum consistent with proposedstructure.

Analysis Calcd for C₁₃ H₁₁ OCl 0.7H₂ O: Calculated: C, 67.51; H, 5.40.Found: C, 67.46; H, 5.31.

M⁺ 218.

EXAMPLE 30 ##STR102##

To a stirred solution of 2-chlorophenol (5 g, 38.9 mmol, Aldrich) andpyridine (3.2 mL, 40 mmol) in methylene chloride (100 mL) was addedbenzoyl chloride (0.1 mL) dropwise over 15 minutes. The solution wasstirred 4 hours at room temperature and then poured onto crushed ice(100 mL), allowed to warm to room temperature and stirred 18 hours. Themixture was extracted with 100 mL of ethyl acetate and the ethyl acetatewas washed with 10% aqueous HCl (25 mL), water (25 mL), 10% aqueous NaOH(25 mL) water (25 mL), saturated brine (25 mL) and dried over MgSO₄.After filtration, the volatile components were removed at reducedpressure on a rotary evaporator. The reaction was assumed to bequantitative (no 2-chlorophenol present upon TLC analysis). This crudebenzoate (1.1 g) without further purification was treated with aluminumchloride (1 g, 7.5 mmol) in small portions over 5 minutes. This mixturewas then heated to 160° C. (oil bath temperature) for 2 hours. Theresulting brown mass was cooled to room temperature and treated withcrushed ice/concentrated HCl (1:1 by volume, total volume 100 mL) for 30minutes. The aqueous mixture was then extracted with two 50 mL portionsof ethyl acetate. The combined extracts were washed twice with 10%aqueous NaOH (25 mL). These base extracts were combined and washed withethyl acetate (25 mL). The base extracts were then acidified by thedropwise addition of concentrated HCl. The resulting precipitate wasfiltered and washed with water This produced 0.63 g (59%) of the titlecompound.

HRMS (M+) for C₁₃ H₉ ³⁵ ClO₂ Calculated: 232.0291 Found: 232.0310

The compounds exemplified in Table 4 were prepared essentially asdescribed in Example 30 with the exception of Example 39 which wasprepared from 2-methoxyphenol, benzoic acid and polyphosphoric acid at120° C. for 1 hour, with the disclosed substitutions being made for2-chlorophenol.

                                      TABLE 4                                     __________________________________________________________________________     ##STR103##                                                                   Ex. No.                                                                           Compound           Ar.sup.2 OH Analysis                                   __________________________________________________________________________    31                                                                                 ##STR104##        3-chlorophenol                                                                            HRMS (M+) for C.sub.13 H.sub.9.sup.36                                         ClO.sub.2  Calc: 232.0291 Found:                                              232.0304                                   32                                                                                 ##STR105##        2-fluorophenol                                                                            HRMS (M+) for C.sub.13 H.sub.9                                                FO.sub.2  Calc: 216.0587 Found:                                               216.0595                                   33                                                                                 ##STR106##        3-fluorophenol                                                                            HRMS (M+) for C.sub.13 H.sub.9                                                FO.sub.2  Cacl: 216.0587 Found:                                               216.0588                                   34                                                                                 ##STR107##        2-methylphenol                                                                            Melting point Found: 173-175°                                          C. Literature: 173-174° C. (J.                                         Am. Chem. Soc., 49, 1029 (1927))           35                                                                                 ##STR108##        3-methylphenol                                                                            HRMS (MH+) for C.sub.14 H.sub.13                                              O.sub.2  Calc: 213.0916 Found:                                                213.0913                                   36                                                                                 ##STR109##        2,6-difluorophenol                                                                        HRMS (M+) for C.sub.13 H.sub.8 F.sub.2                                        O.sub.2  Calc: 234.0492 Found:                                                234.0497                                   37                                                                                 ##STR110##        2,5-difluorophenol                                                                        HRMS (M+) for C.sub.13 H.sub.8 F.sub.2                                        O.sub.2  Calc: 234.0492 Found:                                                234.0494                                   38                                                                                 ##STR111##        2-hydroxymethylbenzoate                                                                   HRMS (M+) for C.sub.16 H.sub.12                                               O.sub.4  Calc: 256.0736 Found:                                                256.0741                                   39                                                                                 ##STR112##        2-methoxyphenol                                                                           HRMS (M+) for C.sub.14 H.sub.12                                               O.sub.3  Calc: 228.0786 Found:             __________________________________________________________________________                                       228.0796                               

EXAMPLE 40 ##STR113##

4-Fluorophenol (8.8 g, 78.5 mmol) and KOH (4 g, 71.3 mmol) were heatedtogether in a round-bottom flask with a bunson burner until the KOHdissolved. A catalytic amount of activated Cu (˜100 mg) was added,followed by 4-iodoanisole (15 g, 64 mmol). The mixture was heated at160° C. for 1.75 hours and poured into cold dilute aqueous NaOH. Thesolution was extracted with 3 portions of ether and the combinedextracts were washed with brine, dried over Na₂ SO₄ and concentrated toprovide the crude product. Flash chromatography on silica gel using 40:1hexane/EtOAc gave the product (3.7 g, 17 mmol) as a colorless oil:

Anal. calc'd for C₁₃ H₁₁ FO₂ : Calculated: C, 71.55; H, 5.08. Found: C,71.44; H, 5.13.

EXAMPLE 41 ##STR114##

The product of Example 40 (1.45 g, 6.64 mmol) was stirred in 40 mL CH₂Cl₂ at -78° C. and 7 mL of 1N BBr₃ in CH₂ Cl₂ was added. After stirringat 0° C. for 30 min and 25° C. for 20 h, the mixture was poured into H₂O. The CH₂ Cl₂ was separated, washed with brine, dried over Na₂ SO₄ andconcentrated. Recrystallization from hexane/CH₂ Cl₂ provided the productas a white solid: mp 91°-94° C.;

Anal. calc'd for C₁₂ H₉ FO₂.0.1 H₂ O: Calculated: C, 69.97; H, 4.50.Found: C, 69.93; H, 4.54.

EXAMPLE 42 ##STR115##

To an excess of phenol (4 g) in a round bottom flask was added K₂ CO₃(3.2 g, 23.2 mmol), CuI (110 mg, 0.58 mmol) and 2-amino-5-bromopyridine.The reaction mixture was stirred at 180° C. for 16 hours, cooled to roomtemperature and diluted with 50 ml of 10% NaOH. The aqueous layer wasextracted with two 40 ml portions of ethyl acetate. The organic layerswere combined, dried, concentrated and chromatographed on a 4 mmchromatotron plate (20% ethyl acetate/80% hexane). The product wasidentified by NMR and used in the next example.

EXAMPLE 43 ##STR116##

To the product of example 42 (1.5 g, 8.1 mmol) in ml of 40N H₂ SO₄ wasadded to NaNO₃ (685 mg, 8.1 mmol) at 0° C. The reaction was then stirredat room temperature for 0.5 hour followed by the addition of 50 ml ofwater. The reaction was extracted with 100 ml of ethyl acetate, theorganic layer dried and the solvent removed in vacuo. Recrystallizationof the crude solid from 50% CH₂ Cl₂ /50% hexane afforded the titlecompound.

EXAMPLE 44 1- 2-(4-phenoxyphenoxy)ethyl!pyrrolidine ##STR117##

A solution of 4-phenoxyphenol (0.56 g, 3.0 mmol),1-(2-chloroethyl)-pyrrolidine HCl (0.51 g, 3.0 mmol) and powdered K₂ CO₃(1.2 g, 8.7 mmol) in 30 mL DMF was stirred at 80°-90° C. for 15 hours.The solution was cooled, poured into Et₂ O and water and the ether layerwashed with water and brine, dried over Na₂ SO₄ and concentrated invacuo to give 0.79 g of a brown oil. The crude product was flashedchromatographed on silica gel using a gradient of 2:1 hexane/EtOAc to100% EtOAc to provide the title compound (0.65 g, 76.5%) as a lightyellow oil:

Analysis calculated for C₁₈ H₂₁ NO₂ : Calculated: C, 76.30; H, 7.47; N,4.94. Found: C, 76.51; H, 7.50; N, 4.84.

The compounds exemplified in the following Table were preparedessentially as described in Example 44 with substitution of theindicated phenol for 4-phenoxyphenol.

                                      TABLE 5                                     __________________________________________________________________________     ##STR118##                                                                   Ex.                                                                           No.                                                                              Compound                     Starting Material                                                                        Analysis                           __________________________________________________________________________    45                                                                                ##STR119##                  4-hydroxydiphenyl- methane                                                               C.sub.19 H.sub.23 NO: Calc: C,                                                81.10; H, 8.24; N, 4.98.                                                      Found: C, 81.10; H, 8.36; N,                                                  4.95.                              46                                                                                ##STR120##                  trans-4-hydroxystilbene                                                                  mp 104-104.5°C.;                                                       C.sub.20 H.sub.23 NO: Calc: C,                                                81.87; H, 7.90; N, 4.77.                                                      Found: C, 81.51; H, 8.02; N,                                                  4.70.                              47                                                                                ##STR121##                  4-hydroxybenzophenone                                                                    C.sub.18 H.sub.21 NO.sub.2.0.1H                                               .sub.2 O: Calc: C, 76.79; H,                                                  7.19; N, 4.71. Found: C,                                                      76.73; H, 7.12; N, 4.66.           48                                                                                ##STR122##                  Ex. 41     C.sub.18 H.sub.20 FNO.sub.2 :                                                 Calc: C, 71.74; H, 6.69; N,                                                   4.65. Found: C, 71.47; H,                                                     6.88; N, 4.47.                     49                                                                                ##STR123##                  Ex. 28     .sup.1 H NMR (CDCl.sub.3) d                                                   1.80(4H, m), 2.63(4H, m),                                                     2.90(2H, t), 4.08(4H, m),                                                     6.84(1H, d), 6.87(2H, d),                                                     7.19(2H, d), 8.66(1H, d);                                                     HRMS, m/z 288.1286 (calc'd for                                                C.sub.18 H.sub.20 SON.sub.2,                                                  288.1296).                         50                                                                                ##STR124##                  4-fluoro-4'-hydroxy- benzophenone                                                        C.sub.19 H.sub.20 FNO.sub.2 :                                                 Calc: C, 72.82; H, 6.43; N,                                                   4.47 Found: C, 72.68; H, 6.75;                                                N, 4.35                            51                                                                                ##STR125##                  4-chloro-4'-hydroxy- benzophenone                                                        C.sub.19 H.sub.20 ClNO.sub.2 :                                                alc: C, 69.19; H, 6.11; N,                                                    4.25; Cl, 10.75 Found: C,                                                     69.28; H, 6.10; N, 4.15; Cl,                                                  10.49                              52                                                                                ##STR126##                  Ex. 30     HRMS (M+) for C.sub.19                                                        H.sub.20.sup.35 ClNO.sub.2                                                    Calc: 329.1183 Found:                                                         329.1186                           53                                                                                ##STR127##                  Ex. 31     HRMS (MH+) for C.sub.19                                                       H.sub.21.sup.35 ClNO.sub.2                                                    Calc: 330.1261 Found:                                                         330.1285                           54                                                                                ##STR128##                  Ex. 32     HRMS (M+) for C.sub.19                                                        H.sub.20 FNO.sub.2  Calc:                                                     313.1478 Found: 313.1490           55                                                                                ##STR129##                  Ex. 33     HRMS (M+) for C.sub.19                                                        H.sub.20 FNO.sub.2  Calc:                                                     313.1478 Found: 313.1479           56                                                                                ##STR130##                  Ex. 34     HRMS (M+) for C.sub.20                                                        H.sub.23 NO.sub.2  Calc:                                                      309.1729 Found: 309.1707           57                                                                                ##STR131##                  Ex. 35     HRMS (M+) for C.sub.20                                                        H.sub.23 NO.sub.2  Calc:                                                      309.1729 Found: 309.1738           58                                                                                ##STR132##                  Ex. 36     HRMS (MH+) for C.sub.19                                                       H.sub.20 F.sub.2 NO.sub.2                                                     Calc: 332.1462 Found:                                                         332.1491                           59                                                                                ##STR133##                  Ex. 37     HRMS (M+) for C.sub.19                                                        H.sub.19 F.sub.2 NO.sub.2                                                     Calc: 331.1384 Found:                                                         331.1371                           60                                                                                ##STR134##                  Ex. 38     HRMS (M+) for C.sub.21                                                        H.sub.23 NO.sub.4  Calc:                                                      353.1627 Found: 353.1601           61                                                                                ##STR135##                  Ex. 39     HRMS (M+) for C.sub.23                                                        H.sub.20 NO.sub.3  Calc:                                                      325.1678 Found: 325.1689           62                                                                                ##STR136##                  4- benzyloxy!phenol                                                                      C.sub.18 H.sub.23 NO.sub.2                                                    0.10H.sub.2 O: Calc: C, 76.27;                                                H, 7.82; N, 4.68. Found: C,                                                   76.09; H, 7.80; N, 4.62.           63                                                                                ##STR137##                  4'-hydroxy-4-biphenyl- carboxylic                                                        C.sub.19 H.sub.22 NO.sub.3                                                    1.1H.sub.2 O: Calc: C, 68.90;                                                 H, 7.06; N, 4.23. Found: C,                                                   68.87; H, 6.75; N, 3.99.           64                                                                                ##STR138##                  4'-hydroxy-4-phenoxy- benzoic                                                            C.sub.19 H.sub.22 NO.sub.4                                                    2.4H.sub.2 O: Calc: C, 61.57;                                                 H, 7.02; N, 3.78. Found: C,                                                   61.72; H, 7.10; N, 3.94.                                                      H.R.M.S. M.sup.+  calcd:                                                      328.1549. Found: 328.1550.         65                                                                                ##STR139##                  Ex. 43     C.sub.17 H.sub.20 N.sub.2                                                     O.sub.2 0.1H.sub.2 O: Calc: C,                                                71.35; H, 7.12; N, 9.79.                                                      Found: C, 71.28; H, 7.31; N,                                                  9.51.                              __________________________________________________________________________

EXAMPLE 66 ##STR140##

The product from Example 46 (0.103 g, 0.35 mmol) was hydrogenated inMeOH (20 mL) with catalytic 4% Pd/C under 5 psi H₂ pressure at 25° C.for 4h. The solution was concentrated and filtered through a plug ofsilica gel using EtOAc to give the title compound (0.093 g, 0.315 mmol)as a colorless oil: ¹ H NMR (CDCl₃) δ 1.83 (4H, m), 2.62 (4H, m), 2.87(6H, m), 4.09 (2H, t), 6.83 (2H, d), 7.08 (2H, d), 7.19 (3H, t), 7.28(2H, t); HRMS, m/z 295.1928 (calc'd for C₂₀ H₂₅ NO, 295.1936).

EXAMPLE 67 ##STR141##

The product from Example 47 (0.5 g, 1.69 mmol), 1,2-ethanedithiol (0.28mL, 3.38 mmol) and BF₃.2AcOH (0.47 mL, 3.38 mmol) were combined andstirred at 25° C. for 21 h. The mixture was poured into EtOAc andaqueous NaHCO₃ and the EtOAc washed with 15% NaOH and brine, dried overNa₂ SO₄ and concentrated to give the crude thioketal. A solution of1,3-dibromo-5,5-dimethylhydantoin (0.48 g, 1.69 mmol) in CH₂ Cl₂ (5 mL)was cooled to -78° C. and hydrogen fluoride-pyridine (0.8 mL, 3.5 mmol)was added, followed by a solution of the thioketal in CH₂ Cl₂ (3 mL).After stirring at -78° C. for 1 h, the mixture was poured into CH₂ Cl₂and aqueous NaHCO₃ and the CH₂ Cl₂ separated, washed with brine, driedover Na₂ SO₄ and concentrated to give the crude product. Flashchromatography on silica gel using a gradient of 2:1 hexane/EtOAc to100% EtOAc provided the title compound (0.108 g, 20%) as a light yellowoil: ¹ H NMR (CDCl₃) d 1.82 (4H, m), 2.65 (4H, m), 2.82 (2H, t), 4.15(2H, t), 6.94 (2H, d), 7.44 (7H, m); HRMS, m/z 317.1583 (calc'd for C₁₉H₂₁ NOF₂, 317.1591).

EXAMPLE 68 ##STR142##

The title compound was prepared in the same manner as Example 44 using4-benzylthiophenol as the starting material and stirring at 80° C. for6.5 h. The crude product was treated with ethanolic HCl to give, afterwashing with ether, the HCl salt as a white solid: mp 137°-139° C.;Anal. calc'd for C₁₉ H₂₃ NS.HCl: C, 68.34; H, 7.24; N, 4.19; Cl, 10.62.Found: C, 68.33; H, 7.27; N, 4.15; Cl, 10.36.

EXAMPLE 69 ##STR143##

A solution of the product from Example 68 (0.5 g, 1.5 mmol) and 80-85%mCPBA (0.32 g, ˜1.5 mmol) in CH₂ Cl₂ (20 mL) was stirred at 0° C. for 2h. The mixture was concentrated and flash chromatographed on silica gelusing a gradient of 100:1:1 to 100:4:1 CH₂ Cl₂ /MeOH/NH₄ OH. The HClsalt was generated with ethanolic HCl to provide, after concentration,the title compound as a white solid: mp 180°-182° C. (d); Anal. calc'dfor C₁₉ H₂₃ NOS.HCl: C, 65.22; H, 6.91; N, 4.00; Cl, 10.13. Found: C,65.16; H, 7.20; N, 3.95; Cl, 9.84.

EXAMPLE 70 ##STR144##

Aminopyridine (586 mg, 6.2 mmol) was dissolved in 2 mL methanol. To thepyridine was added 2 mL 5N HCl/CH₃ OH followed by the aldehyde fromExample 3. Sodium cyanoborohydride (60 mg) was added to the mixturewhich was stirred for 12 hours at RT. The reaction was quenched with 20mL 10% sodium hydroxide and extracted with 3×50 mL ethyl acetate. Thecombined organic phases were dried (MgSO₄), filtered and concentrated toafford a brown oil. The crude product was chromatographed (silica gel,methanol/methylene chloride/ammonium hydroxide 2/97.5//0.5) to giveyellow crystals. The product had the following properties: Anal. calcdfor C₁₈ H₂₄ N₃ O.0.25 H₂ O: C, 71.61; H, 7.85; N, 13.92. Found C, 71.54;H, 7.84; N, 13.78.

EXAMPLE 71 ##STR145##

The title compound was prepared in the same manner as Example 44 using4-phenoxyaniline as the starting material and stirring at 60° C. for 20h, to provide a tan solid. This was dissolved in MeOH and treated withethanolic HCl to provide, after concentration, the HCl salt.Recrystallization afforded a CO₂ complex of the product as white plates:mp 202°-202.5° C.; Anal. calc'd for C₁₈ H₂₂ N₂ O.HCl.CO₂ : C, 62.89; H,6.39; N, 7.72; Cl, 9.77. Found: C, 62.64; H, 6.43; N, 7.59; Cl, 9.81.

EXAMPLE 72 ##STR146##

Oxalyl chloride (0.56 ml, 6.35 mmol) was added to a stirred solution of6-Chloronicotinic acid (1 g, 6.35 mmol; Aldrich) in THF (10 ml). Afterthe addition of a drop of DMF to initiate the reaction, the mixture wasstirred at room temperature for another 10 minutes. The solvent wasremoved in vacuo and the acid chloride was then dissolved in benzene (20ml). AlCl₃ (2.1 g, 15.9 mmol) was then added slowly and the reaction wasstirred at reflux for 1.5 hours. The mixture was then concentrated andflash chromatographed through a pad of silica gel (10% EAℑ90% hexane) toafford 1.35 g. of a pale yellow solid. The resulting product had thefollowing properties:

Analysis calculated for C₁₂ H₈ NOCl: Calculated: C, 66.22; H, 3.70; N,6.44. Found: C, 66.11; H, 3.63; N, 6.32. m.p. 55°-56° C.

EXAMPLE 73 ##STR147##

NaH (75 mg, 1.84 mmol; 60% dispersion) was added to a solution ofpyrrolidinoethanol (450 mg, 1.84 mmol; Aldrich) in benzene (20 ml). Themixture was stirred at room temperature for 10 minutes and then theproduct from example 71 was added and the reaction was allowed to stirfor 4 hours. The reaction was diluted with 50 ml of EA and the organiclayer was washed with 100 ml of H₂ O. The organic layer was dried,concentrated, and chromatographed on a 2 mm chromatotron plate (90 CH₂Cl₂ ℑ4 MeOHℑ1 NH4OH) to afford 480 mg of pure product.

Analysis Calculated for C₁₈ H₂₀ N₂ O₂ 0.2 H₂ O: Calculated: C, 72.07; H,6.85; N, 9.34. Found: C, 72.09; H, 6.89; N, 9.30.

EXAMPLE 74 ##STR148##

1-(2-hydroxyethyl)pyrrolidine (10 mL, 85.5 mmol, Aldrich) was treatedwith sodium hydride (50% dispersion in mineral oil, 0.5 g, 10.4 mmol) insmall portions over 15 minutes and stirred 0.5 hour. To this solutionwas added 2-bromothiazole (1.6 g, 9.6 mmol, Aldrich) and the mixture wasstirred 18 hours at room temperature. The mixture was poured into water(250 mL) and extracted with two 50 mL portions of ethyl acetate. Thecombined ethyl acetate extracts were washed with water (2×50 mL),saturated brine (50 mL) and dried over MgSO₄. After filtration, thevolatile components were removed at reduced pressure on a rotaryevaporator. The residue was chromatographed on silica gel gradienteluting with ether:hexane (1:1 to 100% ether) saturated with aqueousconcentrated ammonium hydroxide. This produced 1.4 g (74%) of the titlecompound.

HRMS (MH+) for C₁₉ H₁₅ N₂ OS calculated: 199.0905 found: 199.0924

EXAMPLE 75 ##STR149##

To a cooled (-40° C.) and stirred solution of the product of Example 74(0.1 g, 0.5 mmol) in tetrahydrofuran (5 mL) was added n-butyllithium(1.6M in THF, 0.38 mL, 0.6 mmol) dropwise over one minute. The mixturewas allowed to warm to 0° C. and stirred for 1 hour. The mixture wasthen treated with benzaldehyde (0.1 mL, 1.0 mmol) and stirred for 15minutes. The mixture was poured into water (25 mL) and extracted with 25mL of ethyl acetate. The ethyl acetate was washed 2 times with water(2×10 mL), saturated brine (10 mL) and dried over MgSO₄. Afterfiltration, the volatile components were removed at reduced pressure ona rotary evaporator. This produced 0.1 g (66%) of the title compound.

HRMS (MH+) for C₁₈ H₂₁ N₂ O₂ S calculated: 305.1324 found: 305.1326

EXAMPLE 76 ##STR150##

The product from Example 75 (0.1 g, 0.33 mmol) was subjected to thereaction conditions described for the preparation of Example 11. Thecrude product was chromatographed on silica gel eluting with ethylacetate:hexane (1:1) saturated with aqueous concentrated ammoniumhydroxide. This produced 0.07 g (74%) of the title compound.

HRMS (MH+) for C₁₆ H₂₁ N₂ OS calculated: 289.1375 found: 289.1373

EXAMPLE 77 ##STR151##

A mixture of 4-Bromophenol (20 g), K₂ CO₃ (35 g),1°(2-Chloroethyl)pyrrolidine •HCl (19.7 g) in DMF was heated to 70° C.overnight. The mixture was cooled to room temperature and quenched withwater, extracted with ethyl acetate. The organic phase was washed withwater (3 times), dried over MgSO₄ and concentrated. The residue waschromatographed over silica gel using EtOH/CH₂ Cl₂ /NH₄ OH (4/95/1) aseluent to give 15 g of title product.

EXAMPLE 78 ##STR152##

1- 2-(4-Bromophenoxy)ethyl!pyrrolidine (540.3 mg, 2 mmol, Aldrich) wasdissolved in dry THF (6 mL) and cooled to -78° C. t-Butyllithium (2.4 mLof 1.8M solution) was added and the reaction was stirred for 4 h underArgon. 3-Pyridinecarboxaldehyde (214.2 mg, 2 mmol, Aldrich) in THF (0.5mL) was added and reaction mixture allowed to warm to r.t. over 1 h.Water was added and the reaction solution was extracted with ethylacetate (3×20 mL). The combined organic layers were washed with brine,dried over Na₂ SO₄, filtered and concentrated in vacuo. The residue waschromatographed on silica gel using CHCl₃ /EtOH/NH₄ OH (95/5/0.5) aseluant to give 220 mg of compound as yellow oil: ¹ H NMR: 300 MHzspectrum consistent with proposed structure. Analysis Calcd for C₁₈ H₂₂N₂ O₂ 0.6H₂ O: C, 69.92; H, 7.56; N, 9.06. Found: c, 69.60; H, 7.31; N,8.94.

The compounds exemplified in the following Table were preparedessentially as described in Example 78.

                                      TABLE 6                                     __________________________________________________________________________     ##STR153##                                                                   Ex.                                                                           No.                                                                              Compound                      Ar.sup.1 Precursor                                                                        Analysis                         __________________________________________________________________________    79                                                                                ##STR154##                   4-pyridinecarboxaldehyde                                                                  C.sub.18 H.sub.22 N.sub.2                                                     O.sub.2 0.2H.sub.2 O: Calc:                                                   C, 71.59; H, 7.48; N, 9.28.                                                   Found: C, 71.63; H, 7.40; N,                                                  9.22.                            80                                                                                ##STR155##                   3-anisaldehyde                                                                            C.sub.20 H.sub.25 NO.sub.3                                                    0.4H.sub.2 O: Calc: C,                                                        71.79; H, 7.77; N, 4.19.                                                      Found: C, 71.64; H, 7.59; N,                                                  4.19. M.sup.+  = 327.            81                                                                                ##STR156##                   4-anisaldehyde                                                                            C.sub.20 H.sub.25 NO.sub.3                                                    0.2H.sub.2 O: Calc: C,                                                        72.57; H, 7.73; N, 4.23.                                                      Found: C, 72.47; H, 7.70; N,                                                  4.51. M.sup.+  = 327.            82                                                                                ##STR157##                   2-anisaldehyde                                                                            C.sub.20 H.sub.25 NO.sub.3                                                    0.8H.sub.2 O: Calc: C,                                                        70.27; H, 7.84; N, 4.10.                                                      Found: C, 70.25; H, 7.72; N,                                                  3.73. M.sup.+  = 327.            83                                                                                ##STR158##                   2-quinolinecarbox- aldehyde                                                               C.sub.22 H.sub.24 N.sub.2                                                     0.4H.sub.2 O: Calc: C,                                                        74.30; H, 7.03; N, 7.80.                                                      Found: C, 74.23; H, 7.47; N,                                                  7.69. M.sup.+  = 348.            84                                                                                ##STR159##                   3-quinolinecarbox- aldehyde                                                               C.sub.22 H.sub.24 O.sub.2                                                     0.3H.sub.2 O: Calc: C,                                                        74.68; H, 7.01; N, 7.92.                                                      Found: C, 74.68; H, 7.08; N,                                                  7.81.                            85                                                                                ##STR160##                   2-thiophenecarbox- aldehyde                                                               C.sub.17 H.sub.21 NOS.sub.2                                                   : Calc: C, 67.29; H, 6.98;                                                    N, 4.62. Found: C, 67.14; H,                                                  6.92; N, 4.56.                   86                                                                                ##STR161##                   3-thiophenecarbox- aldehyde                                                               C.sub.17 H.sub.21 NO.sub.2                                                    S1.2H.sub.2 O: Calc: C,                                                       62.82; H, 7.26; N, 4.31.                                                      Found: C, 62.81; H, 6.81; N,                                                  4.36. M.sup.+  = 303.            87                                                                                ##STR162##                   2-furaldehyde                                                                             C.sub.17 H.sub.21 NO.sub.3                                                    0.2H.sub.2 O: Calc: C,                                                        70.18; H, 7.41 N, 4.81.                                                       Found: C, 69.99; H, 7.19; N,                                                  4.77. M.sup.+  = 287.            88                                                                                ##STR163##                   3-furaldehyde                                                                             C.sub.17 H.sub.21 NO.sub.3                                                    0.3H.sub.2 O: Calc: C,                                                        69.74; H, 7.44 N, 4.78,                                                       Found: C, 69.68;H, 7.13; N,                                                   4.79. M.sup.+  = 287.            89                                                                                ##STR164##                   piperonal   C.sub.20 H.sub.23 NO.sub.4                                                    0.2H.sub.2 O: Calc: C,                                                        69.63; H, 6.84; N, 4.06.                                                      Found: C, 69.75; H, 6.88; N,                                                  4.09. M.sup.+  = 341             90                                                                                ##STR165##                                                                                                  ##STR166## NMR spectrum consistent with                                                  proposed structure                91*                                                                              ##STR167##                                                                                                  ##STR168## C.sub.19 H.sub.22 FNO.sub.2.0                                                 .1H.sub.2 O: Calc: C, 71.95;                                                  H, 7.05; N, 4.41 Found: C,                                                    71.78; H, 7.19; N, 4.43.         92                                                                                ##STR169##                   2-pyridinecarboxaldehyde                                                                  Fully characterized in                                                        example 138.                     93                                                                                ##STR170##                   2-fluorobenzaldehyde                                                                      C.sub.19 H.sub.22 CNO.sub.2.0                                                 .1H.sub.2 O Calc: C, 71.95;                                                   H, 7.05; N, 4.41 Found: C,                                                    71.78; H, 7.19: N, 4.43          94                                                                                ##STR171##                   3-fluorobenzaldehyde                                                                      Fully characterized in                                                        example 142.                     95                                                                                ##STR172##                   3-chlorobenzaldehyde                                                                      Fully characterized in                                                        example 143.                     96                                                                                ##STR173##                   3-fluoro-p-anisaldehyde                                                                   Compound was fully                                                            characterized in the next                                                     step. See Example No.            __________________________________________________________________________                                                 144.                              *Compound of Example 91 was desilylated using the method described in         Example 18                                                               

EXAMPLE 97 ##STR174##

To a solution of thiazole (0.5 g, 5.87 mmol) in THF (15 mL) at 0° C. wasadded 1.6M nBuLi in hexanes (3.75 mL, 6 mmol) and the mixture stirred at0° C. for 15 min. This solution was added to a solution of the productfrom Example 3 (1.1 g, 5.0 mmol) in THF (20 mL) at -78° C. and themixture stirred for 45 min. The reaction mixture was quenched withsaturated NH₄ Cl and poured into ether and water. The ether layer wasseparated, washed with brine, dried over Na₂ SO₄ and concentrated. Flashchromatography on silica gel using a gradient of 100:1:0.5 to 100:2:0.5CH₂ Cl₂ /MeOH/NH₄ OH gave the title compound (1.12 g, 74%) as a lightbrown solid: Anal. calc'd for C₁₆ H₂₀ N₂ O₂ S.0.30 H₂ O: C, 62.03; H,6.70; N, 9.04. Found: C, 62.04; H, 6.64; N, 9.07.

EXAMPLE 98 ##STR175##

To a solution of 2-trimethylsilylthiazole (1.09 g, 6.9 mmol) in THF (25mL) at -78° C. was added 1.6M n-BuLi in hexanes (4.5 mL, 7.2 mmol) andthe mixture warmed to -50° C. for 1 min and cooled to -78° C. A solutionof the product from Example 3 (1.4 g, 6.4 mmol) in THF (6 mL) was addedand the mixture stirred at -78° C. for 45 min. The reaction mixture wasquenched with saturated NH₄ Cl and poured into ether and water. Theether layer was separated, washed with brine, dried over Na₂ SO₄ andconcentrated. Flash chromatography on silica gel using a gradient of100:2:0.5 to 100:3:0.5 CH₂ Cl₂ /MeOH/NH₄ OH gave the title compound(0.42 g).

EXAMPLE 99 ##STR176##

To a stirred solution of the ketone of example 50 (850 mg) in EtOH (25ml) was added water (5 ml), then NaBH₄ (513 mg) was added pinch by pinchand the mixture stirred at room temperature for 2 hours. The reactionmixture was quenched with 1N NaOH, extracted with ethyl acetate, driedover MgSO₄ and concentrated. The residue was chromatographed over silicagel using 4/95/1 EtOH/CH₂ Cl₂ /NH₄ OH to give the title product (500mg).

Analysis Calculated for C₁₉ H₂₁ FNO₂ Calculated: C, 72.35; H, 7.03; N,4.44 Found: C, 72.01; H, 7.01; N, 4.38

                                      TABLE 7                                     __________________________________________________________________________     ##STR177##                                                                   Ex. No.                                                                           Compound                     Starting Ketone                                                                      Analysis                              __________________________________________________________________________    100                                                                                ##STR178##                  Ex. 52 HRMS (MH+) for C.sub.19 H.sub.23.s                                            up.35 ClNO.sub.2  Cacl: 332.1417                                              Found: 332.1410.                      101                                                                                ##STR179##                  Ex. 53 HRMS (MH+) for C.sub.19 H.sub.23.s                                            up.35 ClNO.sub.2  Calc: 332.1417                                              Found: 332.1426                       102                                                                                ##STR180##                  Ex. 54 HRMS (M+) for C.sub.19 H.sub.22                                               FNO.sub.2  Calc: 315.1635 Found:                                              315.1639                              103                                                                                ##STR181##                  Ex. 55 HRMS (M+) for C.sub.19 H.sub.22                                               FNO.sub.2  Calc: 315.1635 Found:                                              315.1628                              104                                                                                ##STR182##                  Ex. 56 HRMS (M+) for C.sub.20 H.sub.25                                               NO.sub.2  Calc: 311.1885 Found:                                               311.1856                              105                                                                                ##STR183##                  Ex. 57 HRMS (M+) for C.sub.20 H.sub.25                                               NO.sub.2  Calc: 311.1885 Found:                                               311.1882                              106                                                                                ##STR184##                  Ex. 58 HRMS (M+) for C.sub.19 H.sub.21                                               F.sub.2 NO.sub.2  Calc: 333.1540                                              Found: 333.1529                       107                                                                                ##STR185##                  Ex. 59 HRMS (M+) for C.sub.19 H.sub.21                                               F.sub.2 NO.sub.2  Calc: 333.1540                                              Found: 333.1548                       108                                                                                ##STR186##                  Ex. 60 HRMS (M+) for C.sub.21 H.sub.25                                               NO.sub.4  Calc: 355.1784 Found:                                               355.1808                              109                                                                                ##STR187##                  Ex. 61 HRMS (M+) for C.sub.20 H.sub.25                                               NO.sub.3  Calc: 327.1834 Found:                                               327.1807                              110                                                                                ##STR188##                  Ex. 51 C.sub.17 H.sub.22 ClNO.sub.2                                                  Calc: C, 68.77; H, 6.68; N, 4.22;                                             l, 10.68 Found: C, 68.48; H,                                                  6.75; N, 4.17; Cl, 10.62              111                                                                                ##STR189##                  Ex. 73 C.sub.18 H.sub.22 N.sub.2 O.sub.2                                             0.4H.sub.2 O: Calc: C, 70.75; H,                                              7.52; N, 9.17. Found: C, 70.63;                                               H, 7.52; N, 9.08.                     __________________________________________________________________________

EXAMPLE 112 ##STR190##

This example demonstrates the reduction of benzylic alcohols usinghydrogenation in the presence of palladium.

The product of example 111 (250 mg, 0.84 mmol) was dissolved in 20 ml of60% MeOHℑ40% acetic acid and transferred to a Parr shaker along with acatalytic amount of 4% PdℑC. The reaction was shaken for 5 hours at roomtemperature under a 5 psi pressure of H₂. The reaction mixture wasfiltered and basified with 10% NaOH. The mixture was extracted with 2 25ml portions of EA which were combined. The organic layer was dried andthe solvent removed in vacuo to afford pure product.

Analysis calculated for C₁₈ H₂₂ N₂₀ 0.25 H₂ O: Calculated: C, 75.36; H,7.91; N, 9.76. Found: C, 75.43; H, 8.13; N, 9.45.

EXAMPLE 113 ##STR191##

This example demonstrates reduction of benzylic alcohols usingtriethylsilane.

To a stirred solution of the product from Example 100 (0.26 g, 0.78mmol) and triethylsilane (1 mL) in methylene chloride (5 mL) was addedtrifluoroacetic acid (0.1 mL) in one portion. This solution was stirred10 minutes at room temperature. The mixture was poured into 5% aqueousNa₂ CO₃ (25 mL) and extracted with 25 mL of ethyl acetate. The ethylacetate was washed 2 times with water (2×10 mL), saturated brine (10 mL)and dried over MgSO₄. After filtration, the volatile components wereremoved at reduced pressure on a rotary evaporator. The crude productwas chromatographed on silica gel gradient eluting with ethylacetate:hexane (1:9 to 1:1) saturated with aqueous concentrated ammoniumhydroxide. This produced 0.22 g (89%) of the title compound.

HRMS (M+) for C₁₉ H₂₂ ³⁵ ClNO Calculated: 315.1390 Found: 315.1385

In the same manner as described in example 112 the compounds describedin Table 8 were reduced.

                                      TABLE 8                                     __________________________________________________________________________     ##STR192##                                                                   Ex.                               Starting                                    No.                                                                              Compound                       Alcohol Analysis                            __________________________________________________________________________    114                                                                               ##STR193##                    Ex. 101 HRMS (M+) for                                                                 C.sub.19 H.sub.22.sup.35 ClNO                                                 Calc: 315.1390 Found: 315.1388      115                                                                               ##STR194##                    Ex. 102 HRMS (M+) for C.sub.19 H.sub.22                                               FNO Calc: 299.1685 Found:                                                     299.1678                            116                                                                               ##STR195##                    Ex. 103 HRMS (M+) for C.sub.19 H.sub.22                                               FNO Calc: 299.1685 Found:                                                     299.1681                            117                                                                               ##STR196##                    Ex. 104 HRMS (M+) for C.sub.20 H.sub.26                                               NO Calc: 295.1936 Found:                                                      295.1945                            118                                                                               ##STR197##                    Ex. 105 HRMS (M+) for C.sub.20 H.sub.25                                               NO Calc: 295.1936 Found:                                                      295.1914                            119                                                                               ##STR198##                    Ex. 106 HRMS (M+) for C.sub.19 H.sub.21                                               F.sub.2 NO Calc: 317.1591                                                     Found: 317.1593                     120                                                                               ##STR199##                    Ex. 107 HRMS (M+) for C.sub.19 H.sub.21                                               F.sub.2 NO Calc: 317.1591                                                     Found: 317.1598                     121                                                                               ##STR200##                    Ex. 97  HRMS. m/z 288.1290 (calc'd for                                                C.sub.16 H.sub.20 SON.sub.2,                                                  288.1297).                          122                                                                               ##STR201##                    Ex. 98  HRMS, m/z 288.1299 (calc'd for                                                C.sub.16 H.sub.20 SON.sub.2,                                                  288.1296).                          123                                                                               ##STR202##                    Ex. 108 HRMS (MH+) for C.sub.21                                                       H.sub.26 NO.sub.3  Calc:                                                      340.1913 Found: 340.1885            124                                                                               ##STR203##                    Ex. 109 HRMS (MH+) for C.sub.20                                                       H.sub.25 NO.sub.2  Calc:                                                      311.1885 Found: 311.1875            125                                                                               ##STR204##                    Ex. 77  C.sub.18 H.sub.22 N.sub.2                                                     O0.2H.sub.2 O: Calc: C, 75.60;                                                H, 7.89; N, 9.80. Found: C,                                                   75.53; H, 7.69; N, 9.58.                                                      M.sup.+  = 282.                     126                                                                               ##STR205##                    Ex. 78  C.sub.18 H.sub.22 N.sub.2                                                     O0.3H.sub.2 O: Calc: C, 75.12;                                                H, 7.92; N, 9.73. Found: C,                                                   74.96; H, 7.14; N, 9.47.                                                      M.sup.+  = 282.                     127                                                                               ##STR206##                    Ex. 79  C.sub.20 H.sub.25 NO.sub.2                                                    0.4H.sub.2 O: Calc: C, 75.39;                                                 H, 8.16; N, 4.40. Found: C,                                                   75.20; H, 8.13; N, 4.43.                                                      M.sup.+ = 311.                      128                                                                               ##STR207##                    Ex. 80  C.sub.20 H.sub.25 NO.sub.2                                                    0.2H.sub.2 O: Calc: C, 76.25;                                                 H1 8.13; N, 4.45. Found: C,                                                   76.11; H, 7.88; N, 4.41.                                                      M.sup.+  = 311.                     129                                                                               ##STR208##                    Ex. 88  C.sub.20 H.sub.25 NO.sub.2 :                                                  Calc: C, 77.14; H, 8.09; N,                                                   4.50. Found: C, 77.18; H, 7.61;                                               N, 4.11. M.sup.+  = 311.            130                                                                               ##STR209##                    Ex. 82  C.sub.20 H.sub.23 NO.sub.4                                                    0.2H.sub.2 O: Calc: C, 89.63;                                                 H, 6.84; N, 4.06. Found: C,                                                   69.75; H, 6.88; N1 4.09.                                                      M.sup.+  = 325.                     131                                                                               ##STR210##                    Ex. 83  M.sup.+  =332.                      132                                                                               ##STR211##                    Ex. 84  C.sub.22 H.sub.24 N.sub.2                                                     O0.5H.sub.2 O: Calc: C, 74.39;                                                H, 7.38; N, 8.20. Found: C,                                                   77.42; H, 7.31; N, 8.26.            133                                                                               ##STR212##                    Ex. 84  C.sub.11 H.sub.21 NOS: Calc: C,                                               71.04; H, 7.34: N, 4.87. Found:                                               C, 70.57; H, 7.45; N, 4.77.                                                   M.sup.+  = 287.                     134                                                                               ##STR213##                    Ex. 85  C.sub.17 H.sub.21 NOS0.2H.sub.2                                               O: Calc: C, 70.16; H, 7.41; N,                                                4.81. Found: C, 70.15; H, 7.07;                                               N, 4.83. M.sup.+  = 287.            135                                                                               ##STR214##                    Ex. 86  M.sup.+  = 271.                     136                                                                               ##STR215##                    Ex. 87  M.sup.+  = 271.                     137                                                                               ##STR216##                    Ex. 90  C.sub.19 H.sub.23 NO.sub.2                                                    0.3H.sub.2 O: Calc: C, 75.37;                                                 H, 7.86; N, 4.63. Found: C,                                                   75.23; H, 7.24; N, 4.14.                                                      M.sup.+  = 297.                     138                                                                               ##STR217##                    Ex. 92* HRMS for C.sub.19 H.sub.22 N                                                  Calc: 282.1732 Found: 282.1726      139                                                                               ##STR218##                    Ex. 99  C.sub.19 H.sub.22 FNO.1/4H.sub.2                                               O Calc: C, 75.10; H, 7.46; N,                                                4.61 Found: C, 75.31; H, 7.32;                                                N, 4.54                             140                                                                               ##STR219##                    Ex. 110 C.sub.19 H.sub.22 NClO Calc: C,                                               72.24; H, 7.02; N, 4.44 Found:                                                C, 72.02; H, 7.34; N, 4.30          141                                                                               ##STR220##                    Ex. 93  C.sub.19 H.sub.22 FNO Calc: C,                                                76.23; H, 7.41; N, 4.69 Found:                                                C, 76.29; H, 7.34; N, 4.64          142                                                                               ##STR221##                    Ex. 94  C.sub.19 H.sub.22 FNO Calc: C,                                                76.2;3; H, 7.41; N, 4.69 Found:                                               C, 76.11; H, 7.67; N, 4.66          143                                                                               ##STR222##                    Ex. 95  C.sub.19 H.sub.22 ClNO.0.25H.sub                                              .2 O Calc: C, 71.24; H, 7.06;                                                 N, 4.37; Cl, 11.07 Found: C,                                                  71.18; H, 7.18; N, 4.38; Cl,                                                  10.95                               144                                                                               ##STR223##                    Ex. 96  C.sub.20 H.sub.24 FNO.sub.2                                                   0.1H.sub.2 O Calc: C, 72.53; H,                                               7.36; N, 4.23 Found: C, 72.42;                                                H, 7.64; N, 4.12 M.sup.+  =         __________________________________________________________________________                                              329                                  *The alcohol of Example 93 was converted to its corresponding acetate wit     Ac.sub.2 O and then hydrogenated                                         

EXAMPLE 145 ##STR224##

To a stirred solution of 15.2 g of 2-benzyloxyethanol in 100 ml of CH₂Cl₂ and 50 ml pyridine was added 20 g of p-toluenesulfonyl chloride and20 mg of N,N-dimethylaminopyridine at 0° C. The mixture was stirred at0° C. for 10 minutes, warmed up to 25° C. and stirred at 25° C. for 4hrs, and concentrated in vacuo. The residue was extracted with ethylacetate, washed with water, dried over Na₂ SO₄ and concentrated in vacuogave crude oily gum which was flash chromatographed on silica to give6.5 g of corresponding tosylate which was reacted with isonipecotamideto provide the title compound following the procedure described inexample 10.

Calcd for C₁₅ H₂₂ N₂ O₂.O.1H₂ O: C, 68.20; H, 8.47; N, 10.61 Found: C,68.28; H, 8.31; N, 10.44

EXAMPLE 146 Preparation of 1- 2-(5-benzoylpyridin-2-yl)oxy!ethyl!-4-piperidinecarboxamide ##STR225##

A solution of 1.5 g of the compound of example 145 in 25 ml of ethanolin a parr shaker was exposed to hydrogen gas at 25° C. at 60 psipressure for 23 hrs. The catalyst was removed by filtration and thefiltrate was concentrated in vacuo to afford an oily gum. To a stirredsolution of 344 mg of the gum in 6 ml of DMF was added 200 mg of 50% NaH(in oil) and the mixture was stirred at 25° C. for 15 minutes undernitrogen atmosphere. 436 mg of the compound of example 73 was added tothe mixture and was stirred at 25° C. for 4 hrs, quenched with water andthe mixture was poured into water and was extracted with ethyl acetate.The organic extract was washed with water, dried over Na₂ SO₄ andconcentrated in vacuo to give 380 mg of oily residue, which waschromatographed on silica gel using 85% CHCl₃, 14% ethanol and 1% NH₄ OHas eluant to provide 14 mg of title compound as white crystaline solid.

Calcd for C₂₀ H₂₃ N₃ O₃.1/4H₂ O: C, 67.11; H, 6.62; N, 11.74 Found: C,67.17; H, 6.94; N, 11.63

EXAMPLE 147 ##STR226##

To a stirred solution of 365 mg of the compound prepared in example 146in 5 ml of ethanol was added 365 mg of NaBH₄ and the mixture was stirredat room temperature for 1 hr. The mixture was poured into water andextracted with ethyl acetate. The organic phase was washed with water,dried over Na₂ SO₄, concentrated in vacuo to yield crude residue. Thecrude residue was chromatographed on silica gel using 80% CHCl₃, 19%ethanol and 1% NH₄ OH as eluant to provide 210 mg of an oily gum. To asolution of the oily gum in 10 ml of ethanol containing 1 ml of glacialacetic acid, in a parr shaker was exposed to hydrogen gas at 25° C. over10% Pd/C catalyst at 5 psi pressure for 6 hrs. The catalyst was removedby filtration and the solvent was removed from the filtrate underreduced pressure to give an oily residue. The oily residue was extractedwith ethyl acetate, washed with 10% K₂ CO₃ solution and water, driedover Na₂ SO₄, concentrated in vacuo to provide a residue which waschromatographed on silica gel using 85% CHCl₃, 14% ethanol and 1% NH₄ OHas eluant to provide 110 mg of the title compound 57 as white solid.

Calcd for C₂₁ H₂₅ N₃ O₂.1/4 H₂ O: C, 69.84; H, 7.47; N, 12.22 Found: C,69.39; H, 7.78; N, 11.98

EXAMPLE 148 ##STR227##

The phenol of example 18 (90 mg, 0.47 mmol) was dissolved in DMF (2 mL).To this was added tetrabutylammonium bromide (16 mg, 0.05 mmol) andethylene carbonate (62 mg, 0.71 mmol). The mixture was heated at 140° C.under Argon for 4 hours. The reaction was cooled to room temperature andthe solvent was removed under reduced pressure. The residue wasdissolved in EtOAc and washed with brine, dried (Na₂ SO₄) andconcentrated to provide the title compound as yellow oil. The resultingproduct had the following properties: ¹ NMR: 300 MHz spectrum consistentwith proposed structure.

Analysis Calculated for C₁₃ H₁₄ O₂ S 0.7H₂ O: Calc: C, 63.23; H, 6.29.Found: C, 63.20; H, 5.83.

M⁺ =234

The compounds exemplified in the following Table were preparedessentially as described in Example 148, except that the phenol ofexample 18 was replaced with the corresponding phenol designated in theTable.

                                      TABLE 9                                     __________________________________________________________________________    Ex. No.                                                                           Compound                   Starting Phenol                                                                      Analysis                                __________________________________________________________________________    149                                                                                ##STR228##                Ex. 19 C.sub.13 H.sub.14 O.sub.2 S Calc:                                             C, 66.64; H, 6.02. Found: C, 66.26;                                           H, 6.16. M.sup.+  = 234                 150                                                                                ##STR229##                Ex. 20 Compound was fully characterized in                                           the next step. See Example No.                                                231.                                    151                                                                                ##STR230##                Ex. 21 C.sub.10 H.sub.18 O.sub.3  Calc: C,                                           74.40; H, 7.02 Found: C, 73.97; H,                                            6.65 M.sup.+  = 258                     152                                                                                ##STR231##                Ex. 22 Compound was fully characterized in                                           the next step; See Example No.                                                233.                                    153                                                                                ##STR232##                Ex. 24 Compound was fully characterized in                                           the next step. See Example No.                                                236.                                    154                                                                                ##STR233##                Ex. 29 Compound was fully characterized in                                           the next step. See Example No.                                                234.                                    155                                                                                ##STR234##                Ex. 25 Compound was fully characterized in                                           the next step. See Example No.                                                235.                                    156                                                                                ##STR235##                Ex. 23 Compound was fully characterized in                                           the next step. See Example No.          __________________________________________________________________________                                          314.                                

EXAMPLE 157 ##STR236##

To a solution of the product from Example 48 (2.04 g, 10 mmol) in 25 mLDMF was added t-butyl bromoacetate (1.9 mL, 11.8 mmol) and catalyticn-Bu₄ NI, followed by 60% NaH dispersion in oil (0.48 g, 12 mmol). Themixture was heated at 60° C. for 3.5 hours and cooled. The mixture waspoured into ether and water and the ether layer separated, washed withbrine, dried over Na₂ SO₄ and concentrated. Flash chromatography onsilica using 20:1 hexane/EtOAc to provide the title compound (2.84 g,89%) as a colorless oil.

Anal. calc'd for C₁₈ H₁₉ FO₄ : Calculated: C, 67.91; H, 6.02. Found: C,67.67; H, 6.18.

                                      TABLE 10                                    __________________________________________________________________________    Ex. No.                                                                           Compound                 Starting Phenol                                                                            Analysis                            __________________________________________________________________________    158                                                                                ##STR237##              4-hydroxy-diphenylmethane                                                                  NMR spectrum consistant with                                                  proposed structure.                 159                                                                                ##STR238##              4-phenoxyphenol                                                                            NMR spectrum consistant with                                                  proposed structure.                 160                                                                                ##STR239##              4-(benzyloxy)phenol                                                                        C.sub.16 H.sub.20 O.sub.4 :                                                   Calc: C, 72.59; H, 7.05. Found:                                               C, 72.28; H, 7.18.                  __________________________________________________________________________

EXAMPLE 161 ##STR240##

To a solution of the product from Example 157 (2.7 g, 8.48 mmol) in THF(50 mL) was added solid LAH (0.38 g, 10 mmol) in portions and themixture stirred at 25° C. for 30 minutes. The mixture was poured intoEtOAc and water and the EtOAc layer separated, washed with brine, driedover Na₂ SO₄ and concentrated to provide the title compound (2.08 g,99%) as a white solid: mp 78°-79° C.;

Anal. calc'd for C₁₄ H₁₃ FO₃.0.2 H₂ O: Calculated: C, 66.77; H, 5.36.Found: C, 66.97; H, 5.38.

                                      TABLE 11                                    __________________________________________________________________________    Ex. No.                                                                           Compound                Starting tBu Ester                                                                    Analysis                                  __________________________________________________________________________    162                                                                                ##STR241##             Ex. 158 NMR spectrum consistent per the                                               proposed structure                        163                                                                                ##STR242##             Ex. 159 NMR spectrum consistent per the                                               proposed structure                        164                                                                                ##STR243##             Ex. 160 C.sub.15 H.sub.16 O.sub.3 0.15H.sub.2                                         O: Calc: C, 72.94; H, 6.65. Found: C,                                         72.92; H, 6.58.                           __________________________________________________________________________

EXAMPLE 165 ##STR244##

To a stirred solution of 4-hydroxy-diphenylmethane (20 g, Aldrich) inCH₂ Cl₂ (100 mL) was added 50% aqueous solution of NaOH (50 mL) followedby allyl bromide (15 mL, Aldrich) and tetraethylammonium bromide (1 g),After 16 hours, the layers were separated. The aqueous phase wasextracted with ether. The combined organic extract was dried over MgSO₄and distilled to give 4-allyloxy-diphenylmethane (16 g). B.p. 130°-135°C./1 mm. This product (16 g) was heated to 230° C. for 8 hours. Aftercooling, the resulting product was taken-up in CHCl₃ (500 mL). Thesolution was stirred and cooled to 0° C. To this was added3-chloroperoxybenzoic acid (16 g, 80-85%, Aldrich) suspended in CHCl₃(100 mL). After 2 hours, the mixture was filtered through celite and thefiltrate washed with saturated NaHCO₃ solution. The organic extract wasdried over MgSO₄, and heated to reflux with 1-methyl-morpholine (10 mL)for 15 minutes. The mixture was concentrated and the residuechromatographed over silica gel using 30% ethyl acetate in hexane togive the title product (10 g) as a colourless thick oil.

EXAMPLE 166 ##STR245##

To a stirred solution of 4-hydroxy-diphenylmethane (25 g, Aldrich) inCH₂ Cl₂ (200 mL) was added 50% aqueous solution of NaOH (50 mL) followedby 3-chloro-2-methylpropene (50 mL, Aldrich) and tetrabutylammoniumbromide (1 g), After 16 hours, the layers were separated. The aqueousphase was extracted with ether. The combined organic extract was driedover MgSO₄ and distilled to give 4-methallyloxy-diphenylmethane (16 g).B.p. 135° C./1 mm. The product (8.8 g) was heated to 215°-220° C. for 8hours. After cooling, the resulting product was chromatgraphed oversilica gel using 6% ethyl acetate in hexane to give the correspondingrearranged product (8 g). This material was taken-up in CHCl₃ (500 mL).The solution was stirred and cooled to 0° C. To this was added Na₂ CO₃(4 g) and 3-chloroperoxybenzoic acid (9 g, 80-85%, Aldrich) suspended inCHCl₃ (100 mL). After 4.5 hours, the mixture was filtered through celiteand the filtrate washed with 5% aqueous Na₂ CO₃ solution. The organicextract was dried over MgSO₄ and concentrated to 100 mL. To thissolution was added para-toluenesulphonic acid (0.5 g) and the mixturelet stand at room temperature for 16 hours. The solution was thenconcentrated and the residue chromatographed over silica gel using 30%ethyl acetate in hexane to give the title product (10 g) as a colorlessthick oil.

EXAMPLE 167 ##STR246##

A 60% mineral oil suspension of sodium hydride (1.9 g) was washed withhexane and suspended in THF (200 mL) at -78° C. To this stirred solutionwas added allyl alcohol (3 mL). After 1 hour, the product of Example 73was added in one lot and the mixture stirred for 16 hours. Then allylalcohol (5 mL) was added and the mixture refluxed for 0.25 hours. Themixture was cooled, washed with water, dried over MgSO₄ and concentratedto give a thick liquid. A solution of this material in diphenylether (20ml) was heated to reflux for 5 hours. The mixture was cooled andchromatographed over silica gel using 80-100% ethyl acetate in hexane togive the title product (1.8 g) as a white solid.

EXAMPLE 168 ##STR247##

To a stirred solution of the product of Example-167 (1.1 g) in CHCl₃ (20mL) at 0° C. was added 3-chloroperoxybenzoic acid (1.5 g, 50-60%,Aldrich) suspended in CHCl₃ (5 mL). After 2 hours, 3-chloroperoxybenzoicacid (0.5 g, 80-85%, Aldrich) was added to the reaction mixture. After 4hours, the mixture was allowed to warm to room temperature over 1 hr.The mixture was washed with 5% aqueous K₂ CO₃ solution, dried over MgSO₄and concentrated. The residue was chromatographed over silica gel using50% ethyl acetate in hexane as eluant to give a mixture of an epoxideand the title product. This mixture in ethyl acetate (20 mL) was allowedto stand at room temperature with para-toluenesulfonic acid (20 mg) for16 hours. The solution was washed with water, dried over MgSO₄ andconcentrated to give the title product as a white solid (0.85 g).

EXAMPLE 169 ##STR248##

To a stirred solution of the product of Example 168 (0.8 g) in THF (50mL) was added sodium borohydride (0.4 g) and the mixture refluxed for 1hour. The mixture was treated with saturated aqueous NH₄ Cl with cautionand extracted with ethyl acetate. The organic phase was washed withwater, dried over MgSO₄ to give the title product as a colorless solid.

EXAMPLE 170 ##STR249##

The product of Example 169 was hydrogenated in a parr apparatus in amixture of ethyl acetate and acetic acid over 5% Pd on carbon under 5psi hydrogen atmosphere at room temperature for 3 hours. The reactionmixture was filtered and the filtrate concentrated. The residue waschromatographed over silica gel using ethyl acetate as eluant to givethe title product as a colorless solid (0.3 g).

EXAMPLE 171 ##STR250##

A 35% mineral oil suspension of potassium hydride (12 g) was washed withhexane and suspended in THF (150 mL) at -78° C. The mixture was stirredand 4-hydroxydiphenylmethane (18.5 g) was added as solid in severalportions over 0.5 hours. The mixture was allowed to warm to 0° C. over 2hours and cooled back to -78° C. To this was addeddiethylcarbamoylchloride (13.6 g, Aldrich) over 0.25 hours and themixture allowed to warm to room temperature over 16 hours. The mixturewas refluxed for 0.5 hours and cooled in ice. To this was added waterand the organic phase was dried over MgSO₄ and distilled to give thetitle product as a colorless liquid. B.p. 170°-175° C./0.05 mm.

EXAMPLE 172 ##STR251##

To a stirred solution the product of Example 171 (5.085 g) in ether (150mL) and tetramethylethylene-diamine (3 mL) at -78° C. was added a 1.3molar solution of sec.butyl lithium in cyclohexane (16 mL). After 1hour, dimethylforamide (1.45 mL) was added. After 2 hours, saturatedaqueous NH₄ Cl was added and the layers separated. The organic phase wasdried over MgSO₄ and concentrated. The residue was chromatographed oversilica gel using 20% ethyl acetate in hexane to to give the titleproduct as thick oil (5.1 g).

EXAMPLE 173 ##STR252##

The product of Example 172 was taken-up in ether (125 mL) and thesolution cooled to -78° C. To this stirred solution was added a 1N ethersolution of allylmagnesium bromide (16 mL). After 10 minutes, themixture was warmed to 0° C. and quenched carefully with saturatedaqueous NH₄ Cl. The layers were separated and the organic phase wasdried over MgSO₄ and concentrated. The residue was chromatographed oversilica gel using 20% to 30% ethyl acetate in hexane to give the titleproduct as a thick gum (3.9 g).

EXAMPLE 174 ##STR253##

To a stirred solution of the product of Example 173 (1.24 g) in THF (30mL) at 0° C. was added sulfur trioxide-pyridine complex (0.812 g,Aldrich). After 0.5 hours, the mixture was allowed to stand at 4° C. for16 hours. Then the mixture was stirred at 0° C. for 4 hours and cooledto -78° C. To this mixture was added lithium aluminium hydride (1 g) inone lot. The mixture was allowed to warmed to 0° C. over 1 hour, then toroom temperature over 3 hours. To this was added, carefully, water andthen excess of 1N HCl. The mixture was extracted with ether. Thecombined organic extract was dried and concentrated to give the titleproduct as a thick gum (0.38 g).

EXAMPLE 175 ##STR254##

To a stirred solution of the product of Example-174 (0.38 g) in CHCl₃ (5mL) at 0° C. was added 3-chloroperoxybenzoic acid (0.38 g, 80-85%,Aldrich) suspended in CHCl₃ (3 mL). After 1 hour 3-chloroperoxybenzoicacid (0.38 g, 80-85%, Aldrich) was added. After 1 hour, the mixture waswashed with saturated NaHCO₃. The organic phase was dried by gravityfiltration and concentrated. The residue was chromatographed over silicagel using 20% ethyl acetate in hexane to give the title product as acolorless gum (0.18 g).

EXAMPLE 176 ##STR255##

A solution of the product of Example 175 (0.18 g) andpara-toluenesulphonic acid (5 mg) in CHCl₃ (5 mL) was allowed to standat room temperature for 16 hours. The solution was washed with water anddried over MgSO₄ to give the title product as a thick gum.

EXAMPLE 177 ##STR256##

The procedure of Example 166 was repeated using 4-phenoxyphenol(Aldrich) and allyl bromide in the place of 4-hydroxy-diphenylmethaneand 3-chloro-2-methylpropane respectively to obtain the title compoundas a thick liquid.

EXAMPLE 178 ##STR257##

4-Phenoxyphenol (4.66 g, 25 mmol), 3-chloro-1-propanol (2.51 g, 26.5mmol), and tetrabutylammonium iodide (82 mg, 0.22 mmol) were dissolvedin 50 mL DMF. Sodium hydride (1.33 g, 33.2 mmol, 60% dispersion inmineral oil) was added slowly to the reaction mixture which was stirredat 60° C. for 12 hours. The reaction was poured into 400 mL water andextracted with 4×150 mL ethyl acetate. The combined organic phases weredried (MgSO₄), filtered and concentrated to afford a brown oil. Thecrude oil was chromatographed (silica gel, 20% ethyl acetate/hexane) togive the pure product as white crystals (3.58 g, 59%). The product hadthe following properties: Anal. calcd for C₁₅ H₁₆ O₃ : C, 73.75; H,6.60. Found C, 73.36: H, 6.65.

EXAMPLE 179 ##STR258##

The alcohol of example 148 (90 mg, 0.38 mmols) was dissolved in amixture of CH₂ Cl₂ (2 mL) and pyridine. The solution was cooled to 0°under Argon, and then p-toluenesulfonyl chloride (87 mg, 0.46 mmol)followed by DMAP (3 mg) were added to the mixture. The reaction mixturewas stirred at 0° C. for 0.5 hours, and then warmed up to roomtemperature and stirred for 16 hours. The solvent was removed underreduced pressure. The residue was dissolved in ether, washed withsaturated KHSO₄ and brine, dried (Na₂ SO₄) and filtered. The filtratewas concentrated to give 120 mg of the title compound as yellow oil.

The compounds in Table 12 were made in an analogous manner. Theresulting product was fully characterized in the next step. See ExampleNo. 229.

                                      TABLE 12                                    __________________________________________________________________________    Ex. No.                                                                           Compound                   Starting Alcohol                                                                      Analysis                               __________________________________________________________________________    180                                                                                ##STR259##                Ex. 165 Compound was characterized by NMR                                             and structure confirmed by the                                                analysis of compound of Example                                               282                                    181                                                                                ##STR260##                Ex. 166 Compound was characterized by NMR                                             and structure confirmed by the                                                analysis of compound of Example                                               285                                    182                                                                                ##STR261##                Ex. 170 Compound was characterized by NMR                                             and structure confirmed by the                                                analysis of compound of Example                                               287                                    183                                                                                ##STR262##                Ex. 178 Compound was characterized by NMR                                             and structure confirmed by the                                                analysis of compound of Example                                               293                                    184                                                                                ##STR263##                Ex. 178 Compound was characterized by NMR                                             and structure confirmed by the                                                analysis of compound of Example                                               350                                    185                                                                                ##STR264##                Ex. 177 Compound was characterized by NMR                                             and structure confirmed by the                                                analysis of compound of Example                                               291                                    186                                                                                ##STR265##                Ex. 162 Compound was fully characterized                                              in the next step. See Example No.                                             238.                                   187                                                                                ##STR266##                Ex. 161 C.sub.21 H.sub.19 SFO.sub.5 :                                                 Calc: C, 62.68; H, 4.76. Found: C,                                            62.73; H, 4.85.                        188                                                                                ##STR267##                Ex. 163 Compound was fully characterized                                              in the next step. See Example No.                                             252.                                   189                                                                                ##STR268##                Ex. 164 Compound was fully characterized                                              in the next step. See Example No.                                             198.                                   190                                                                                ##STR269##                Ex. 149 Compound was fully characterized                                              in the next step. See Example No.                                             230.                                   191                                                                                ##STR270##                Ex. 150 Compound was fully characterized                                              in the next step. See Example No.                                             231.                                   192                                                                                ##STR271##                Ex. 151 Compound was fully characterized                                              in the next step. See Example No.                                             232.                                   193                                                                                ##STR272##                Ex. 152 Compound was fully characterized                                              in the next step. See Example No.                                             233.                                   194                                                                                ##STR273##                Ex. 154 C.sub.21 H.sub.19 FO.sub.5 : Calc:                                            C, 62.68; H, 4.76. Found: C,                                                  62.73; H, 4.85.                        195                                                                                ##STR274##                Ex. 163 Compound was fully characterized                                              in the next step. See Example No.                                             235.                                   196                                                                                ##STR275##                Ex. 153 Compound was fully characterized                                              in the next step. See Example No.                                             236.                                   197                                                                                ##STR276##                Ex. 88  Compound was fully characterized                                              in the next step. See Example No.                                             314.                                   __________________________________________________________________________

EXAMPLE 198 ##STR277##

4-(Benzyloxy)phenol (0.41 g, 2.05 mmol), 1-(2-chloroethyl)pyrrolidinehydrochloride (0.36 g, 2.1 mmol) and powdered potassium carbonate (1.09g, 7.9 mmol) were stirred in 23 mL of N,N-dimethylformamide at 80° C.for 12 hours. The reaction was cooled to room temperature and pouredinto 300 mL water. The aqueous phase was extracted with 4×50 mL ethylacetate. The combined organic washes were dried (NaSO₄), filtered, andconcentrated to afford 0.43 g amber oil. The crude product waschromatographed (silica gel, 20% methanol/heptane) to give the pureproduct (0.39 g, 64%) as a pale yellow solid. The product had thefollowing properties:

Analysis calculated for C₁₉ H₂₃ NO₂.0.10 H₂ O: Calc: C, 76.27; H, 7.82;N, 4.68. Found: C, 76.09; H, 7.80; N, 4.62.

EXAMPLE 199 ##STR278##

The product from Example 198 (2.78 g, 9.3 mmol) was dissolved in 35 mLTHF in a Parr Shaker apparatus. A catalytic amount of 4% Pd/C was added,and the reaction was run under 60 p.s.i. of H₂ at room temperature for23 hours. The reaction was filtered through Celite and concentrated toafford the product (1.49 g, 78%) as yellow crystals. The product had thefollowing properties: mp 113°-115°.

Analysis calculated for C₁₂ H₁₇ NO₂.0.25H₂ O: Calc: C, 68.06; H, 8.33;N, 6.61. Found: C, 68.16; H, 8.06; N, 6.55.

EXAMPLE 200 ##STR279##

2-(Bromomethyl)naphthalene (0.36 g, 1.6 mmol), the phenol from Example199 (0.33 g, 1.6 mmol) and powdered potassium carbonate (0.52, 3.8 mmol)were stirred in 15 mL DMF at 80° for 12 hours. The reaction was cooledto room temperature and poured into 200 mL water. The aqueous phase wasextracted with 4×30 mL ethyl acetate. The combined organic washes weredried (NaSO₄), filtered, and concentrated to afford a tan solid whichwas recrystallized from ethyl acetate/hexane to give the pure product(67 mg, 12%). The product had the following properties:

H.R.M.S. M⁺ calculated for C₂₃ H₂₅ NO₂ : Calc: 347.1886. Found:347.1856.

The compounds exemplified in the following Table were preparedessentially as described in Example 200 except that2-(Bromoethyl)naphthalene was replaced by the designated Ar¹ Precursor.

                                      TABLE 13                                    __________________________________________________________________________    Ex. No.                                                                           Compound                       Ar.sup.1 Precursor                                                                         Chrom.                        __________________________________________________________________________    201                                                                                ##STR280##                    2-(chloromethyl)quinoline monohydrochlo                                       ride         silica gel, methanol/                                                         methylene chloride/                                                           ammonium hydroxide                                                            2/97/1                        202                                                                                ##STR281##                    4-(chloromethyl)-2- methylthiazole                                            hydrochloride                                                                              silica gel, methanol/                                                         methylene chloride/                                                           ammonium hydroxide                                                            2/97/1                        203                                                                                ##STR282##                    4-bromobenzyl bromide                                                                      80% ethyl acetate/hexane/                                                     race triethylamine            204                                                                                ##STR283##                    2,6-dichlorobenzyl bromide                                                                 5% methanol/ethyl                                                             acetate/trace triethylamin                                                    e                             205                                                                                ##STR284##                    4-Fluorobenzyl chloride                                                                    5% methanol/ethyl                                                             acetate/trace triethylamin                                                    e                             206                                                                                ##STR285##                    3-Chlorobenzyl chloride                                                                    silica gel, 70% ethyl                                                         acetate/hexane/trace                                                          triethylamine                 207                                                                                ##STR286##                    2-Fluorobenzyl chloride                                                                    5% methanol/ethyl                                                             acetate/trace triethylamin                                                    e                             208                                                                                ##STR287##                    2-Chlorobenzyl chloride                                                                    5% methanol/ethyl                                                             acetate/trace triethylamin                                                    e                             209                                                                                ##STR288##                    α'-Chloro-α,α,α                                       -trifluoro-m- xylene                                                                       10% methanol/ethyl                                                            acetate/trace triethylamin                                                    e                             210                                                                                ##STR289##                    α-bromo-o-xylene                                                                     5% methanol/ethyl                                                             acetate/trace triethylamin                                                    e                             211                                                                                ##STR290##                    3-Fluorobenzyl chloride                                                                    ethanol/methylene                                                             chloride/ammonium                                                             hydroxide 5/94/1              212                                                                                ##STR291##                    α-chloro-p-xylene                                                                    ethanol/methylene                                                             chloride/ammonium                                                             hydroxide 1/98/1              213                                                                                ##STR292##                    4-Methoxybenzyl chloride                                                                   ethanol/methylene                                                             chloride/ammonium                                                             hydroxide 2.5/97/0.5)         214                                                                                ##STR293##                    1-(chloromethyl)- naphthalene                                                              ethanol/methylene                                                             chloride/ammonium                                                             hydroxide                     __________________________________________________________________________                                                    5/94/1)                                                               Ex. No.                                                                           Analysis                          __________________________________________________________________________                                            201 C.sub.22 H.sub.24 N.sub.2                                                     O.sub.2 0.75H.sub.2 O:                                                        Calc: C, 73.00; H, 7.10; N,                                                   7.74.                                                                         Found: C, 73.08; H, 7.12; N,                                                  7.56.                                                                     202 C.sub.17 H.sub.22 N.sub.2                                                     O.sub.2 0.30H.sub.2 O:                                                        Calc: C, 63.05; H, 7.03; N,                                                   8.65.                                                                         Found: C, 63.09; H, 7.12; N,                                                  8.63.                                                                     203 C.sub.19 H.sub.22 NO.sub.2                                                    Br0.25H.sub.2 O:                                                              Calc: C, 59.92; H, 5.96; N,                                                   3.68.                                                                         Found: C, 59.92; H, 5.76; N,                                                  3.68.                                                                     204 C.sub.19 H.sub.21 NO.sub.2                                                    Cl.sub.2 :                                                                    Calc: C, 62.30; H, 5.78; N,                                                   3.82.                                                                         Found: C, 61.99; H, 5.57; N,                                                  3.79.                                                                     205 C.sub.19 H.sub.22 NO.sub.2                                                    F0.10H.sub.2 O:                                                               Calc: C, 71.74; H, 7.07; N,                                                   4.40.                                                                         Found: C, 71.70; H, 7.01; N,                                                  4.35.                                                                     206 C.sub.19 H.sub.22 NO.sub.2                                                    Cl:                                                                           Calc: C, 68.77; H, 6.68; N,                                                   4.22.                                                                         Found: C, 68.57; H, 6.60; N,                                                  4.15.                                                                     207 C.sub.19 H.sub.22 NO.sub.2                                                    F0.60H.sub.2 O:                                                               Calc: C, 69.96; H, 7.17; N,                                                   4.29.                                                                         Found: C, 69.98; H, 6.97; N,                                                  4.23.                                                                     208 C.sub.19 H.sub.22 NO.sub.2                                                    Cl0.25H.sub.2 O:                                                              Calc: C, 67.85; H, 6.74; N,                                                   4.16.                                                                         Found: C, 67.98; H, 6.68; N,                                                  4.16.                                                                     209 C.sub.20 H.sub.22 NO.sub.2                                                    F.sub.3 :                                                                     Calc: C, 65.74; H, 6.07; N,                                                   3.83.                                                                         Found: C, 65.45; H, 6.04; N,                                                  3.56.                                                                     210 C.sub.20 H.sub.26 NO.sub.2                                                    0.60H.sub.2 O:                                                                Calc: C, 74.55; H, 8.20; N,                                                   4.35.                                                                         Found: C, 74.51; H, 8.18; N,                                                  4.87.                                                                     211 C.sub.19 H.sub.23 NO.sub.2                                                    F0.20H.sub.2 O:                                                               Calc: C, 71.54; H, 7.08; N,                                                   4.39.                                                                         Fond: C, 71.63; H, 7.19; N,                                                   4.34.                                                                     212 C.sub.20 H.sub.25 NO.sub.2                                                    0.15H.sub.2 O:                                                                Calc: C, 76.47; H, 8.12; N,                                                   4.46.                                                                         Found: C, 76.48; H, 8.22; N,                                                  4.38.                                                                     213 C.sub.20 H.sub.26 N.sub.3                                                     0.85H.sub.2 O:                                                                Calc: C, 70.09; H, 7.85; N,                                                   4.09.                                                                         Found: C, 70.07; H, 7.47; N,                                                  4.04.                                                                     214 C.sub.23 H.sub.26 NO.sub.2                                                    0.15H.sub.2 O:                                                                Calc: C, 78.89; H, 7.28; N,                                                   4.00.                                                                         Found: C, 78.89; H, 7.37; N,                                                  3.90.                             __________________________________________________________________________

EXAMPLE 215 ##STR294##

2-Thiophenemethanol (4.18 g, 36.6 mmol), tosyl chloride (7.09 g, 37.2mmol) and pyridine (3 mL, 37.1 mmol) were stirred in 100 mL methylenechloride at RT for 12 hours. The reaction was poured into 200 mL water.The phases were separated, and the organic phase was washed with 2×200mL 10% HCl, 2×200 mL water, and dried (Na₂ SO₄). The resultant crudetosylate (1.05 g, 3.9 mmol) was reacted with the phenol from Example 199(0.34 g, 1.7 mmol) and sodium hydride (0.11 g, 2.8 mmol, 60% dispersionin mineral oil) in 25 mL DMF at RT overnight. The reaction was pouredinto 100 mL water and washed with 4×50 mL ethyl acetate. The organicphases were dried (Na₂ SO₄) and concentrated to afford an amber oil. Thecrude product was chromatographed (silica gel, ethanol/methylenechloride/ammonium hydroxide 5/94/1) to give an amber oil. The producthad the following properties:

Analysis calculated for C₁₇ H₂₁ NO₂ S.0.15 H₂ O: Calc: C, 66.70; H,7.01; N, 4.58. Found: C, 66.72; H, 6.94; N, 4.47.

EXAMPLE 216 ##STR295##

4-Hydroxydiphenyl methane (Aldrich) 1.84 g in 50 ml dimethylformamide(DMF) was added sodium hydride (60% dispersion in mineral oil) 0.5 g(Aldrich) portionwise at R.T. during 15 min. The reaction mixture wasstirred for 1/2 hr and 1.57 g of 1-bromo-3-chloro propane (Aldrich) in10 ml of DMF was added dropwise during 10 min and the mixture wasstirred at room temperature overnight.

Diethyl ether 100 ml and 3 ml of water was added to the reaction mixtureand the organic phase was further washed with H₂ O (10 ml×2), dried,filtered, the solvent removed in vacuo, and the organic material waschromatographed over silica gel using 5% EtOAc in hexane and gave thetitle compound as colorless thick oil 2.1 g.

                                      TABLE 14                                    __________________________________________________________________________     ##STR296##                                                                   Ex. No.                                                                           Compound                   Starting Phenol                                                                           Analysis                           __________________________________________________________________________    217                                                                                ##STR297##                4-hydroxydiphenyl methane                                                                 .sup.1 H NMR: 400 MHz Compound                                                was fully characterized in the                                                next step. See Example No.                                                    226.                               218                                                                                ##STR298##                4-phenoxyphenol                                                                           .sup.1 H NMR: 300 MHz Compound                                                was fully characterized in the                                                next step. See Example No.                                                    250.                               219                                                                                ##STR299##                4-phenoxyphenol                                                                           .sup.1 H NMR: 300 MHz              220                                                                                ##STR300##                Ex. 19      M.sup.+  = 266.                    221                                                                                ##STR301##                Ex. 18      Compound was fully                                                            characterized in the next                                                     step. See Example No. 327.         222                                                                                ##STR302##                Ex. 25      M.sup.+  = 278.                    223                                                                                ##STR303##                Ex. 24      M.sup.+  = 261.                    224                                                                                ##STR304##                Ex. 41      NMR spectrum consistent with                                                  proposed structure.                __________________________________________________________________________

EXAMPLE 225 (METHOD A) Methyl 1- 2-4-(phenylmethyl)phenoxy!ethyl!-2S-pyrrolidine-2-carboxylate,monohydrochloride, hydrate ##STR305##

To a stirred solution of 165 mg of L-proline methyl ester hydrochloridein 5 ml of N,N-dimethylformamide was added 500 mg of powdered potassiumcarbonate and the mixture was stirred under a nitrogen atmosphere atroom temperature for 10 minutes. 382 mg of the compound of example 186was added to the mixture and was heated to 65° and stirred under anitrogen atmosphere for 4 hrs. The mixture was cooled to roomtemperature and the solvent was removed by evaporation under reducedpressure to give crude oily gum, which was extracted with ethyl acetateand was washed with water, dried over sodium sulfate and concentrated invacuo to give crude product which was chromatographed on silica using75% toluene, 25% ethyl acetate as mobile phase to yield 180 mg of oilygum which was converted into its HCl salt using 6N HCl: Dioxane andcrystallization from ether gave 158 mg of the title compound as whitecrystalline solid.

Analysis Calculated for C₂₁ H₂₅ NO₃ HCl H₂ O: Calculated: C, 64.03; H,7.16; N, 3.56. Found: C, 63.76; H, 7.14; N, 3.51.

EXAMPLE 226 (METHOD B) Preparation of 1- 3-4-(phenylmethyl)phenoxy!propyl!-4-piperidinecarboxamide ##STR306##

To a stirred solution of 260.5 mg of the compound of example 216 in 5 mlof N,N-dimethylformamide was added 300 mg of powdered K₂ CO₃ and wasstirred under nitrogen atmosphere for 10 minutes. 150 mg ofisonipecotamide was added to the mixture and it was heated to 65° C. andwas stirred at 65° C. under nitrogen atmosphere for 4 hours. The mixturewas cooled to room temperature and solvent was removed by evaporationunder reduced pressure to give crude oily gum which was dissolved inethyl acetate and was washed with water, dried over sodium sulfate andconcentrated in vacuo to give crude product, which upon crystallizationfrom diethyl ether gave the title compound.

Analysis Calculated C₂₂ H₂₈ N₂ O₂.1/4 H₂ O: Calculated: C, 74.02; H,8.05; N, 7.85 Found: C, 73.98; H, 8.19; N, 7.72

EXAMPLE 227 (METHOD C) ##STR307##

To a stirred suspension of 3-acetamido pyrrolidine (260 mg,) andpotassium carbonate (700 mg, finely divided) in DMF (15 ml), Tosylate ofexample 186 (700 mg) was added. The reaction mixture was heated at 60°C. for 10 hours, evaporated and the residue partitioned between ethylacetate and sat potassium carbonate solution. The ethyl acetate layerwas separated, dried (Na₂ SO₄) and evaporated to afford a yellow oilthat was further purified by radial chromatography on silica (eluant;methylene chloride/ethanol, 97/3) to yield a clear oil (400 mg).

The resulting oil was further purified by crystallization as its HClsalt (ethanol/diethyl ether) to afford the title compound (400 mg).

Analysis Calculated for C₂₁ H₂₆ N₂ O₂.1 HCl: Calculated: C, 67.28; H,7.26; N, 7.47. Found: C, 67.47; H, 7.97; N, 6.88.

EXAMPLE 228 (METHOD D) Phenylmethyl 1- 3-4-(phenylmethyl)phenoxy!propyl!-L-prolinate ##STR308##

To product of example 216 (0.27 g) and 240 mg L-proline benzyl esterhydrochloride in 5 ml DMF was added powdered K₂ CO₃ 280 mg, sodiumiodide 50 mg. The reaction mixture was heated at 80° overnight undernitrogen.

It was then cooled to room temperature and 50 ml of ether and 3 ml ofwater were added. The organic phase was further washed with water (10ml×2) and dried. It was filtered and solvent was removed under vacuo.The residue was chromatographed over silica gel using 10:90:1EtOAc:hexane:Et₃ N to give the title compound as colorless oil. 0.32 gwas obtained.

Analysis for C₂₈ H₃ NO₃ : Calculated: C, 78.29; H, 7.27; N, 3.26. Found:C, 78.42; H, 7.15; N, 3.10. ##STR309##

    TABLE 15                                                                         - Ex.   Method/ Isol'n/                                                        No. AR.sup.1  Q  Ar.sup.2  Y  R                                                Z ZH Prep Chrom. Analysis                                                      229                                                                            ##STR310##                                                                     A A C.sub.19 H.sub.24 N.sub.2 O.sub.2 S.0.3H.sub.2 OCalc: C, 65.22; H,        7.09; N, 8.01.Found: C, 65.30; H, 6.99; N, 7.92.                               230                                                                             ##STR311##                                                                     ##STR312##                                                                     A A C.sub.19 H.sub.24 N.sub.2 O.sub.2 S:Calc: C, 66.25; H, 7.02; N,           8.13.Found: C, 65.91; H, 7.04; N, 8.03.                                        231                                                                             ##STR313##                                                                     ##STR314##                                                                     A A C.sub.19 H.sub.23 N.sub.3 O.sub.2 S1.2H.sub.2 O:Calc: C, 58.90; H,        6.97; N, 11.45.Found: C, 58.78; H, 6.87; N, 11.38.M.sup.+  = 345                                                                                232            ##STR315##                                                                     ##STR316##                                                                     A A C.sub.22 H.sub.27 N.sub.2 O.sub.3 0.3H.sub.2 O:Calc: C, 70.68; H,         7.71; N, 7.49.Found: C, 70.70; H, 7.16; N, 7.34.                               233                                                                             ##STR317##                                                                     ##STR318##                                                                     A A C.sub.21 H.sub.25 FN.sub.2 O.sub.2 :Calc: C, 70.76; H, 7.07; N,           7.66.Found: C, 70.52; H, 6.96; N, 7.66.M.sup.+  =                               356.                                                                                                                           234                            ##STR319##                                                                     ##STR320##                                                                     A A C.sub.21 H.sub.25 ClN.sub.2 O.sub.2.0.2H.sub.2 O:Calc: C, 66.99; H,       6.80; N, 7.44.Found: C, 66.77; H.6.61; N, 7.33.M.sup.+  =                       372.                                                                                                                                   235                    ##STR321##                                                                     ##STR322##                                                                     A A C.sub.21 H.sub.25 FN.sub.2 O.sub.2 0.2H.sub.2 O:Calc: C, 70.06; H,        7.11; N, 7.78.Found: C, 70.17; H, 7.35; N, 7.78.M.sup.+  =                      356.                                                                                                                                    236                   ##STR323##                                                                     ##STR324##                                                                     A A C.sub.20 H.sub.25 N.sub.3 O.sub.2 0.2H.sub.2 O:Calc: C, 70.03; H,         7.46; N, 12.25.Found: C, 69.82; H, 7.43; N, 12.18.M.sup.+  = 339.                                                                                237           ##STR325##                                                                     ##STR326##                                                                     A B C.sub.21 H.sub.25 NO.sub.3 HClH.sub.2 O:Calc: C, 64.03; H, 7.16; N,       3.56.Found: C, 63.76; H, 7.14; N, 3.51.                                        238                                                                             ##STR327##                                                                     ##STR328##                                                                     A B C.sub.22 H.sub.28 N.sub.2 O.sub.2 :Calc: C, 74.97; H, 8.01; N,      F     7.95.ound: C, 74.66; H, 7.66; N, 7.82.                                         239                                                                             ##STR329##                                                                     ##STR330##                                                                     A B C.sub.21 H.sub.26 N.sub.2 O.sub.2 :Calc: C, 74.53; H, 7.74; N,      F     8.28.ound: C, 74.18; H, 7.88; N, 8.25.                                         240                                                                             ##STR331##                                                                     ##STR332##                                                                     A B C.sub.21 H.sub.27 NO.HCl:Calc: C, 72.91; H, 8.16; N, 4.05.Found: C,       72.60; H, 8.30; N, 4.07.                                                       241                                                                             ##STR333##                                                                     ##STR334##                                                                     A B C.sub.20 H.sub.25 NO.HCl:Calc: C, 72.38; H, 7.98; N, 4.22.Found: C,       72.31; H, 7.94; N, 4.17.                                                       242                                                                             ##STR335##                                                                     ##STR336##                                                                     B C C.sub.22 H.sub.28 N.sub.2 O.sub.2.1/4H.sub.2 O:Calc: C, 74.02; H,         8.05; N, 7.85Found: C, 73.98; H, 8.19; N, 7.72                                 243                                                                             ##STR337##                                                                     ##STR338##                                                                     A B C.sub.21 H.sub.26 N.sub.2 O.sub.2 :Calc: C, 73.74; H, 7.78; N,      F     8.19.ound: C, 73.91; H, 7.87; N, 8.16.                                         244                                                                             ##STR339##                                                                     ##STR340##                                                                     B C C.sub.22 H.sub.27 N.sub.2 O.sub.2 :Calc: C, 74.97; H, 8.01; N,      F     7.95.ound: C,74.66; H, 8.41; N, 7.89.                                          245                                                                             ##STR341##                                                                     ##STR342##                                                                     A B C.sub.23 H.sub.29                                                          NO.sub.3.HCl:Calc: C, 68.39; H, 7.49; N, 3.47.Found: C, 68.20; H, 7.56;       N, 3.49.                                                                       246                                                                             ##STR343##                                                                     ##STR344##                                                                     A B C.sub.22 H.sub.27                                                          NO.sub.3.HCl:Calc: C, 67.77; H, 7.25; N, 3.59.Found: C, 67.52; H, 7.20;       N, 3.55.                                                                       247                                                                             ##STR345##                                                                     ##STR346##                                                                     A B C.sub.20 H.sub.25                                                          NO.sub.2.HCl:Calc: C, 69.05; H, 7.53; N, 4.03Found: C, 68.97; H, 7.47;        N, 3.96                                                                        248                                                                             ##STR347##                                                                     ##STR348##                                                                     A B C.sub.28 H.sub.30 N.sub.2 O.sub.3.1/4H.sub.2 O:Calc: C, 75.87; H,         6.70; N, 6.10Found: C, 75.83; H, 6.99; N, 6.14                                 249                                                                             ##STR349##                                                                     Ex. 482 A B C.sub.26 H.sub.34 N.sub.2 O.sub.4.1/4H.sub.2 O:Calc: C,           70.48; H, 7.85; N, 6.32Found: C, 70.39; H, 7.81; N, 6.25                       250                                                                             ##STR350##                                                                     ##STR351##                                                                     A B C.sub.21 H.sub.26 N.sub.2 O.sub.3 :Calc: C, 71.16; H, 7.39; N,            7.9Found: C, 70.86; H, 7.65; N, 7.73                                           251                                                                             ##STR352##                                                                     ##STR353##                                                                     B C C.sub.22 H.sub.28 N.sub.2 O.sub.2 :Calc: C, 74.97; H, 8.01; N,            7.95Found: C, 74.66; H, 8A1; N, 7.89                                           252                                                                             ##STR354##                                                                     ##STR355##                                                                     B C C.sub.20 H.sub.24 N.sub.2 O.sub.3 :Calc: C, 70.57; H, 7.11; N,            8.23Found: C, 70.40; H, 6.93; N, 8.17                                          253                                                                             ##STR356##                                                                     ##STR357##                                                                     B C C.sub.20 H.sub.24 N.sub.2 O.sub.3.1/4H.sub.2 O:Calc: C, 69.64; H,         7.16; N, 8.12Found: C, 69.53; H, 7.29; N, 7.95                                 254                                                                             ##STR358##                                                                     ##STR359##                                                                     B C C.sub.22 H.sub.27                                                          NO.sub.4.HCl:Calc: C, 65.1U; H, 6.95; N, 3.45Found: C, 64.78; H, 6.64;        N, 3.42                                                                        255                                                                             ##STR360##                                                                     ##STR361##                                                                     B C C.sub.21 H.sub.26 N.sub.2 O.sub.3 :Calc: C, 71.16; H, 7.39; N,            7.90Found: C, 70.88; H, 7.69; N, 7.87                                          256                                                                             ##STR362##                                                                     ##STR363##                                                                     C D C.sub.21 H.sub.26 N.sub.2 O.sub.2.1HClCalc: C, 67.28, H, 7.26, N,         7.47.Found: C, 67.47, H, 7.97, N, 8.88.                                        257                                                                             ##STR364##                                                                     ##STR365##                                                                     C D C.sub.19 H.sub.23 NO.sub.2,1HCl, 0.25H.sub.2 O:Calc: C, 67.45; H,         7.30; N, 4.14.Found: C, 67.42; H, 7.28; N, 4.05.                               258                                                                             ##STR366##                                                                     ##STR367##                                                                     D E C.sub.28 H.sub.3 NO.sub.3 :Calc: C, 78.29; H, 7.27; N, 3.26Found:         C, 78.42; H, 7.15; N,3.10                                                      259                                                                             ##STR368##                                                                     ##STR369##                                                                     D F C.sub.20 H.sub.25 NO:Calc: C, 81.31; H, 8.53; N, 4.74Found: C,            81.33; H, 8.84; N, 4.57                                                        260                                                                             ##STR370##                                                                     ##STR371##                                                                     D G C.sub.25 H.sub.32 NO.sub.3.0.2H.sub.2 O:Calc: C, 75.42; H, 8.20; N,       3.52Found: C, 75.12; H, 8.49; N, 3.44                                          261                                                                             ##STR372##                                                                     ##STR373##                                                                     D E C.sub.26 H.sub.28 NO.sub.3 :Calc: C, 77.58; H, 7.01; N, 3.48Found:        C, 77.26; H, 7.23; N, 3.46                                                     262                                                                             ##STR374##                                                                     ##STR375##                                                                     D H C.sub.23 H.sub.27 NO.sub.4 :Calc: C, 72.42; H.7.13; N, 3.67Found:         C, 71.95; H, 6.86; N, 4.16                                                     263                                                                             ##STR376##                                                                     ##STR377##                                                                     D I C.sub.26 H.sub.35 NO.sub.3 :Calc: C, 76.25; H, 8.61; N, 3.42Found:        C, 76.04; H, 8.76; N, 3.37                                                     264                                                                             ##STR378##                                                                     ##STR379##                                                                     D F C.sub.20 H.sub.25 NO.sub.3 :Calc: C, 73.37; H, 7.70; N, 4.28Found:        C, 73.33; H, 7.83; N, 4.25                                                     265                                                                             ##STR380##                                                                     ##STR381##                                                                     D J C.sub.21 H.sub.27 NO3.0.H.sub.2 O:Calc: C, 73.10; H, 8.00; N,             4.06Found: C, 72.91; H, 7.97; N, 4.20                                          266                                                                             ##STR382##                                                                     ##STR383##                                                                     D I C.sub.25 H.sub.17 NO.sub.3.02H.sub.2 O:Calc: C, 76.39; H, 7.03; N,        3.56Found: C, 76.10; H, 7.05; N, 3.48                                          267                                                                             ##STR384##                                                                     ##STR385##                                                                     D J C.sub.20 H.sub.25 NO.sub.3.0.2H.sub.2 O:Calc: C, 72.57; H, 7.73; N,       4.23Found: C, 72.67; H, 7.73; N, 4.19                                          268                                                                             ##STR386##                                                                     ##STR387##                                                                     D A C.sub.23 H.sub.13 NO.sub.3.0.3H.sub.2 O:Calc: C, 73.69; H, 8.50; N,       3.74Found: C, 73.62; H, 8.61; N, 3.70                                          269                                                                             ##STR388##                                                                     ##STR389##                                                                     D E C.sub.24 H.sub.31 NO.sub.3 :Calc: C, 75.56; H, 8.19; N, 3.67Found:        C, 75.32; H, 8.38; N, 3.63                                                     270                                                                             ##STR390##                                                                     ##STR391##                                                                     D E C.sub.23 H.sub.28 NO.sub.3.0.1H.sub.2 O:Calc: C, 74.81; H, 7.97; N,       3.79Found: C, 74.60; H, 8.00; N, 3.77                                          271                                                                             ##STR392##                                                                     ##STR393##                                                                     B E C.sub.26 H.sub.28 N.sub.2 O5, M.sup.+  448 from Massspectrometry          NMR consistant with thestructure.                                              272                                                                             ##STR394##                                                                     ##STR395##                                                                     D E C.sub.22 H.sub.29 NO.sub.2 :Calc: C, 74.33; H, 8.22; N, 3.94Found:        C, 74.21; H, 8.23; N, 3.86                                                     273                                                                             ##STR396##                                                                     ##STR397##                                                                     D E C{hd 27H.sub.31 NO.sub.3.0.2H.sub.2 O:Calc: C, 77.70; H, 7.51; N,         3.33Found: C, 78.47; H, 7.77; N, 3.16                                          274                                                                             ##STR398##                                                                     ##STR399##                                                                     D F C.sub.23 H.sub.31 NO.sub.3.0.1H.sub.2 O:Calc: C, 74.40; H, 8.47; N,       3.77Found: C, 74.19; H, 8.55; N, 3.72                                          275                                                                             ##STR400##                                                                     Ex. 479 B L C.sub.22 H.sub.27 NO.sub.3 0.50H.sub.2 O:Calc: C, 72.90; H,       7.79; N, 3.86.Found: C, 72.97; H, 7.95; N, 3.92.                               276                                                                             ##STR401##                                                                     Ex. 581 B M .sup.1 H NMR (CDCl.sub.3) d 2.12 (2H, q), 2.61 (1H,               q),2.71-2.97 (4H, m), 3.04 (2H, m), 3.69 (3H, s),3.92 (2H, s), 4.06 (2H,       t), 6.63 (2H, d), 7.09(2H, d), 7.18 (3H, m), 7.27 (2H, t); HRMS,m/z            339.1831 (calc'd for C.sub.21 H.sub.25                                          NO.sub.3,339.1834).                                                                                                 277                                       ##STR402##                                                                     ##STR403##                                                                     B N C.sub.21 H.sub.25 N.HCl.0.25H.sub.2 O:Calc: C, 75.88; H, 8.04; N,         4.21; Cl, 10.67.Found: C, 76.06; H, 8.28; N, 4.29; Cl, 10.53.                  278                                                                             ##STR404##                                                                     Ex. 474 B N C.sub.21 H.sub.26 N.HCl.0.30H.sub.2 O:Calc: C, 75.68; H,          8.04; N, 4.20; Cl, 10.64.Found: C, 75.88; H, 8.19; N, 4.28; Cl, 10.35.         279                                                                             ##STR405##                                                                     Ex. 443 B N C.sub.21 H.sub.26 N.sub.2 O.sub.2.1.1HCl.0.1H.sub.2 O:Calc:       C, 66.31; H, 7.23; N, 7.37; Cl, 10.25Found: C, 66.17; H, 7.51; N, 7.31;        Cl, 10.21                                                                      280                                                                             ##STR406##                                                                     ##STR407##                                                                     B N C.sub.20 H.sub.23 NO.1.1HCl.0.5H.sub.2 O:Calc: C, 69.76; H, 7.36;         N, 4.07; Cl, 11.84Found: C, 69.97; H, 7.38; N, 4.01; Cl, 11.95                 281                                                                             ##STR408##                                                                     ##STR409##                                                                     B N C.sub.22 H.sub.26 N.sub.2 O.sub.2.0.25H.sub.2 O:Calc: C, 74.44; H,        7.53; N, 7.89Found: C, 74.59; H, 7.4i; N, 7.78                                 282                                                                             ##STR410##                                                                     ##STR411##                                                                     B N C.sub.24 H.sub.29 NO.sub.3.HClCalc: C, 69.30; H, 7.27; N, 3.37, Cl,       8.52Found: C, 69.20; H, 7.28; N, 3.27; Cl, 8.81                                283                                                                             ##STR412##                                                                     Ex. 474 B N C.sub.25 H.sub.29 NO.sub.3.HCl.H.sub.2 O:Calc: C, 67.35; H,       7.23; N, 3.14, Cl, 7.95Found: C, 67.38; H,6.86; N, 3.14; Cl, 7.98                                                                                284           ##STR413##                                                                     Ex. 443 B N                                                                   285                                                                             ##STR414##                                                                     ##STR415##                                                                     B N C.sub.22 H.sub.26 N.sub.2 O.sub.2.HCl.H.sub.2 O:Calc: C, 65.25; H,        7.22; N, 6.92; Cl, 8.76Found: C, 65.50; H, 7.13; N, 6.61; Cl, 8.87                                                                                286          ##STR416##                                                                     ##STR417##                                                                     B N C.sub.23 H.sub.28 N.sub.2 O.sub.2.1.25H.sub.2 O:Calc: C, 71.38; H,        7.94; N, 7.24Found: C, 71.68; H, 7.81; N, 7.26                                 287                                                                             ##STR418##                                                                     ##STR419##                                                                     B N C.sub.18 H.sub.22 N.sub.2 O.1.9HCl.0.5H.sub.2 O:Calc: C, 61.23; H,        6.73; N, 7.52; Cl, 18.07Found: C, 61.60; H, 6.50; N, 7.60; Cl, 18.37                                                                                288        ##STR420##                                                                     ##STR421##                                                                     V N C.sub.21 H.sub.25 N.sub.3 O.sub.2 :Calc: C, 71.77; H, 7.17; N,      F     11.96ound: C, 72.14; H, 7.l1; N, 11.98                                         289                                                                             ##STR422##                                                                     ##STR423##                                                                     B N C.sub.19 H.sub.21 NO.sub.2.1HCl:Calc: C, 68.77; H, 6.68; N, 4.22;         Cl, 10.67Found: C, 68.32; H, 7.08; N, 4.08; Cl, 10.72                          290                                                                             ##STR424##                                                                     ##STR425##                                                                     B N C.sub.19 H.sub.21 NO.sub.2.1HCl:Calc: C, 71.57; H, 6.86; N,               7.95Found: C, 71.32; H, 7.20; N, 7.83                                          291                                                                             ##STR426##                                                                     ##STR427##                                                                     B N C.sub.23 H.sub.27 NO.sub.4.1HCl:Calc: C, 66.10; H, 6.75; N, 3.35;         Cl, 8.48Found: C, 66.23; H, 7.02; N, 3.25; Cl, 8.43                            292                                                                             ##STR428##                                                                     ##STR429##                                                                     B N C.sub.21 H.sub.25 NO.HCl:Calc: C, 73.34; H, 7.62; N, 4.07; Cl,      F     10.31ound: C, 73.08; H, 7.98; N, 4.15; Cl, 10.23                               293                                                                             ##STR430##                                                                     ##STR431##                                                                     B N C.sub.23 H.sub.28 N.sub.2 O.sub.2.HCl.0.25H.sub.2 O:Calc: C, 68.13;       H, 7.33; N, 6.91; Cl, 8.74Found: C, 68.12; H, 7.23; N, 6.77; Cl, 8.76          294                                                                             ##STR432##                                                                     ##STR433##                                                                     B N C.sub.22 H.sub.26 N.sub.2 O.sub.2.HCl.H.sub.2 O:Calc: C, 65.25; H,        7.22; N, 6.92; Cl, 8.76Found: C, 65.50; H, 7.13; N, 6.61; Cl, 8.87                                                                                295          ##STR434##                                                                     ##STR435##                                                                     A N C.sub.23 H.sub.28 N.sub.2 O.sub.2.0.25H.sub.2 OCalc: C, 74.87; H,         7.79; N, 7.95Found: C, 74.49; H, 7.98; N, 7.46                                 296                                                                             ##STR436##                                                                     ##STR437##                                                                     A N C.sub.22 H.sub.26 N.sub.2 O.sub.3.0.25H.sub.2 OCalc: C, 71.23; H,         7.20; N, 7.55.Found: C, 71.00; H, 7.17; N, 7.47.                               297                                                                             ##STR438##                                                                     Ex. 468 A L C.sub.22 H.sub.27 N.sub.2 O.sub.2.0.25H.sub.2 OCalc: C,           74.02; H, 8.05; N, 7.85.Found: C, 74.29; H, 7.99; N, 7.45.                     298                                                                             ##STR439##                                                                     Ex.469 A A C.sub.24 H.sub.13 NO.sub.3 :Calc: C, 75.66; H, 8.19; N,      F     3.67.ound: C, 75.23; H, 7.99; N, 3.65.                                         299                                                                             ##STR440##                                                                     Ex. 470 A A C.sub.23 H.sub.30 N.sub.2 O.sub.2.0.6H.sub.2 O:Calc: C,           73.22; H, 8.33; N, 7.42.Found: C, 73.05; H, 8.25; N, 7.41                      300                                                                             ##STR441##                                                                     ##STR442##                                                                     A A C.sub.23 H.sub.29 NO.sub.4.HCl0.25H.sub.2 O:Calc: C, 65.08; H,            7.24; N, 3.30.Found: C, 65.28; H, 7.07; N, 3.53.                               301                                                                             ##STR443##                                                                     ##STR444##                                                                     A A C.sub.24 H.sub.31                                                          NO.sub.3.HCl:Calc: C, 68.97; H, 7.72; N, 3.35.Found: C, 69.52; H, 7.81;       N, 3.46.                                                                       302                                                                             ##STR445##                                                                     ##STR446##                                                                     B A C.sub.25 H.sub.33 NO.sub.3.HCl0.25H.sub.2 O:Calc: C, 68.79; H,            7.97; N, 3.21.Found: C, 69.00; H, 8.12; N, 3.26.                               303                                                                             ##STR447##                                                                     ##STR448##                                                                     A K C.sub.23 H.sub.27 NO.sub.2 :Calc: C, 79.05; H, 7.79; N, 4.01.Found:       C, 78.80; H, 7.61; N, 3.98.                                                    304                                                                             ##STR449##                                                                     Ex. 489 A K C.sub.24 H.sub.28 NO.sub.3 :Calc: C, 75.96; H, 7.70; N,           3.69.Found: C, 75.68; H, 8.08; N, 3.63.                                        305                                                                             ##STR450##                                                                     Ex. 494 A K C.sub.22 H.sub.27 NO.sub.4 :Calc: C, 11.52; H, 7.37; N,           3.79.Found: C, 71.44; H, 7.66; N, 3.77.                                        306                                                                             ##STR451##                                                                     Ex. 494 B K C.sub.22 H.sub.25 NO.sub.5.HCl.0.25H.sub.2 OCalc: C, 62.26;       H, 6.29; N, 3.30; Cl, 8.35.Found: C, 62.00; H, 6.44; N, 3.23; Cl, 8.66.        307                                                                             ##STR452##                                                                     Ex. 492 A K C.sub.24 H.sub.29 NO.sub.3 :Calc: C, 75.96; H, 7.70; N,           3.69.Found: C, 75.57; H, 7.80; N, 3.68.                                        308                                                                             ##STR453##                                                                     Ex. 506 A K .sup.1 H NMR 300 MHzCompound was fully characterized in           thenext step. See Example No. 440.                                             309                                                                             ##STR454##                                                                     ##STR455##                                                                     A A C.sub.23 H.sub.28 O.sub.3                                                  NF:Calc: C, 71.66; H, 7.32; N, 3.63.Found: C, 71.63; H, 7.58; N,              3.65.M.sup.+  =                                                                 385                                                                                          310                                                              ##STR456##                                                                     ##STR457##                                                                     A A C.sub.21 H.sub.27 SNO.sub.3                                                :Calc: C, 67.53; H, 7.29; N, 3.75.Found: C, 67.47; H, 7.35; N, 3.62.M.su      p.+  =                                                                          373                                                                                311                                                                        ##STR458##                                                                     ##STR459##                                                                     A A C.sub.22 H.sub.28 O.sub.3 N.sub.2 0.25H.sub.2 O:Calc: C, 70.85; H,        7.70; N, 7.51.Found: C, 70.86; H, 7.59; N, 7.13.M.sup.+  =                      368                                                                                                                                     312                   ##STR460##                                                                     ##STR461##                                                                     A A C.sub.23 H.sub.28 NFO.sub.3 0.1H.sub.2 O:Calc: C, 71.33; H, 7.34;         N, 3.62.Found: C, 71.19; H, 7.34; N, 3.52.M.sup.+  =                            386                                                                                                                               313                         ##STR462##                                                                     ##STR463##                                                                     A A C.sub.21 H.sub.27 SNO.sub.3                                                :Calc: C, 67.53; H, 7.29; N, 3.75.Found: C, 67.22; H, 7.05; N, 3.65.M.su      p.+  =                                                                          373                                                                                314                                                                        ##STR464##                                                                     ##STR465##                                                                     A A C.sub.22 H.sub.27 N.sub.2 O.sub.3 F0.3H.sub.2 O:Calc: C, 67.43; H,        7.10; N, 7.15.Found: C, 67.41; H, 7.23; N, 7.07.M.sup.+  =                      386                                                                                                                                     315                   ##STR466##                                                                     Ex.512 A A C.sub.24 H.sub.32 N.sub.2 O.sub.2 :Calc: C, 75.25; H, 8.48;        N, 7.36.Found: C, 75.41; H.8.48; N, 7.18.                                      316                                                                             ##STR467##                                                                     Ex.508 A A C.sub.23 H.sub.30 N.sub.2 O.sub.2 0.5H.sub.2 O:Calc: C,            73.57; H, 8.32; N, 7.46.Found: C, 73.30; H, 8.02; N, 7.31.                     317                                                                             ##STR468##                                                                     Ex.510 A A C.sub.24 H.sub.31 NO.sub.3.1HCl0.5H.sub.2 O:Calc: C, 67.51;        H.7.79; N, 3.28.Found: C, 67.54; H, 7.72; N, 3.17.                             318                                                                             ##STR469##                                                                     ##STR470##                                                                     D F C.sub.19 H.sub.23 NO.sub.3 :Calc: C, 72.82; H, 7.40; N, 4.47.Found:       C, 72.56; H, 7.79; N, 4.38.                                                    319                                                                             ##STR471##                                                                     ##STR472##                                                                     D F C.sub.24 H.sub.25 NO.sub.3 :Calc: C, 76.78; H, 6.71; N, 3.73.Found:       C, 76.38; H, 6.34; N, 3.77.                                                    320                                                                             ##STR473##                                                                     ##STR474##                                                                     D F C.sub.21 H.sub.27 NO.sub.3 :Calc: C, 73.87; H, 7.97; N, 4.10.Found:       C, 73.71; H, 8.21; N, 4.01.                                                    321                                                                             ##STR475##                                                                     ##STR476##                                                                     A G C.sub.22 H.sub.29 NO.sub.3.0.5H.sub.2 O:Calc: C, 72.50; H, 8.30; N,       3.84.Found: C, 72.46; H, 8.14; N, 3.80.                                        322                                                                             ##STR477##                                                                     ##STR478##                                                                     A G C.sub.27 H.sub.31 NO.sub.3.0.2H.sub.2 O:Calc: C, 77.00; H, 7.51; N,       3.33.Found: C, 76.47; H, 7.77; N, 3.16.                                        323                                                                             ##STR479##                                                                     ##STR480##                                                                     A G C.sub.22 H.sub.27 N.sub.2 O.sub.3 F0.3H.sub.2 O:Calc: C, 67.43; H,        7.10; N, 7.15.Found: C, 67.41; H, 7.23; N, 7.07.                               324                                                                             ##STR481##                                                                     ##STR482##                                                                     A G C.sub.18 H.sub.23 NO.sub.3 :Calc: C, 72.82; H, 7.40; N, 4.47.Found:       C, 73.04; H, 7.64; N, 4.45.                                                    325                                                                             ##STR483##                                                                     Ex. 486 A A C.sub.23 H.sub.27 NO.sub.3.HCl:Calc: C, 68.73; H, 7.02; N,        3.48.Found: C, 68.88; H, 7.16; N, 3.39.                                        ISOLATION/PURIFICATION PROCEDURES                                              A. 84/15/1 CHCl.sub.3 /EtOH/NH.sub.4 OH                                        B. 75/25 Toluene/Ethyl Acetate                                                 C. Crystallization from Et.sub.2 O                                             D. 97/3 Methylene Chloride/Ethanol                                             E. 10/90/1 EtOAc:Hexane:NEt.sub.3                                              F. 99/1 EtOAc/NEt.sub.3                                                        G. 20/80/1 EtOAc/Toluene/TEA                                                   H. 1/1 EtOAc/Heptane                                                           I. 50:50:1 EtOAc/Toluene/TEA                                                   J. 10:1:1 EtOH/EtOAc/TEA                                                       K. 1/98.5/0.5 MeOH/CH.sub.2 Cl.sub.2 /NH.sub.4 OH                              L. 3/97/trace EtOH/EtOAc/NH.sub.4 OH                                           M. 100:0.5:0.5 CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                             N. 85/14/1 CHCl.sub.3 /EtOH/NH.sub.4 OH                                   

EXAMPLE 326 ##STR484##

To a stirred solution of methylamine (40% solution in H₂ O, Aldrich)(13.7 mL, 180 mmol) was added a solution of example 220 (0.47 g, 1.8mmol, in CH₃ CN 5 mL). The resulting mixture was heated to 45°-50° C.for 4-5 hours and then allowed to stir at r.t. for 15 hours. Thereaction was concentrated in vacuo and the aqueous residue extractedwith EtOAc (2×15 mL). The organic layers were combined and acidifiedwith 1N HCl to PH 1 at 0° C. A white precipitate was formed, and thesolid was collected by vacuum filtration. The solid was washed with 1NHCl, followed by hexane to afford 0.35 g salt. The solid was dissolvedin 10% NaOH (30 mL) and extracted with Et₂ O (2×20 mL). The organiclayers were combined, dried over Na₂ SO₄, and concentrated in vacuo togive the free amine as a clear colorless oil (0.3 g). The resultingproduct was fully characterized in the next step. See Example No. 330.

                                      TA8LE 16                                    __________________________________________________________________________    Ex.                                                                           No.                                                                              Compound                          Starting Material                                                                     Analysis                         __________________________________________________________________________    327                                                                               ##STR485##                       Ex. 221 M.sup.+  = 261                   328                                                                               ##STR486##                       Ex. 222 M.sup.+  = 273                   329                                                                               ##STR487##                       Ex. 223 M.sup.+  = 256                   __________________________________________________________________________

EXAMPLE 330 ##STR488##

To a stirred solution of example 326 (0.30 g, 1.1 mmol in CH₂ Cl₂ (6 mL)was added methyl acrylate (Aldrich, 0.13 mL, 1.5 mmol) at r.t. Thereaction was allowed to stir at r.t. for 17 hours, and then concentratedunder a stream of nitrogen gas. The residue was purified by columnchromatography using 10% MeOH/CH₂ Cl₂ as eluant to afford 0.32 g of thetitle compound as a clear colorless oil. The resulting product had thefollowing properties: Analysis calcd for C₁₉ H₂₅ NO₃ S: C, 65.58; H,7.25; N, 4.03. Found: C, 65.38; H, 7.30; N, 3.95.

                                      TABLE 17                                    __________________________________________________________________________    Ex. No.                                                                           Compound                          Starting Material                                                                     Analysis                        __________________________________________________________________________    331                                                                                ##STR489##                       Ex. 327 C.sub.19 H.sub.25 NO.sub.2                                                    S0.2H.sub.2 O: Calc: C,                                                       65.00; H, 7.29; N, 3.99.                                                      Found: C, 64.94; H, 7.19;                                                     N, 3.90. M.sup.+  = 347         332                                                                                ##STR490##                       Ex. 328 C.sub.21 H.sub.26 O.sub.3                                                     NF0.25H.sub.2 O: Calc: C,                                                     69.30; H, 7.34; N, 3.85.                                                      Found: C, 69.26; H, 7.41;                                                     N, 3.77. M.sup.+  = 359         333                                                                                ##STR491##                       Ex. 329 C.sub.20 H.sub.28 N.sub.2                                                     O.sub.3 : Calc: C, 70.15;                                                     H, 7.65; N, 8.18. Found: C,                                                   69.82; H, 7.47; N, 7.99.                                                      M.sup.+  = 324                  __________________________________________________________________________

EXAMPLE 334 ##STR492##

To a stirred solution of example 330 (80 mg, 0.23 mmol) was added 6N HCl(1 mL). The reaction was heated to 70° C. for 4 hours, then concentratedin vacuo to give a white solid. The solid was slurried with Et2O andcollected by vacuum filtration to give 110 mg of the title compound. Theresulting product had the following properties: Analysis calcd for C₁₉H₂₄ NO₃ SCl 1.3 H₂ O: C, 56.30; H, 6.01; N, 3.46. Found: C, 56.05; H,6.22; N, 3.37.

                                      TABLE 18                                    __________________________________________________________________________    Ex. No.                                                                           Compound                          Starting Material                                                                     Analysis                        __________________________________________________________________________    335                                                                                ##STR493##                       Ex. 331 C.sub.18 H.sub.24 NO.sub.3                                                    SCl: Calc: C, 58.45; H,                                                       6.54; N, 3.79. Found: C,                                                      58.12; H, 6.30; N, 3.65.                                                      M.sup.+  = 333                  336                                                                                ##STR494##                       Ex. 332 C.sub.20 H.sub.25 FNO.sub.3                                                   Cl: Calc: C, 62.90; H,                                                        6.60; N, 3.67. Found: C,                                                      62.43; H, 6.72; N, 3.58.                                                      M.sup.+  = 345                  __________________________________________________________________________

EXAMPLE 337 ##STR495##

A mixture of the product of Example 180 (0.48 g), N-benzylpiperazine (1mL), K₂ CO₃ (0.7 g) in DMF (4 mL) was heated to 80° C. for 16 hr. Thevolatiles were removed in vacuo and the residue was extracted with ethylacetate and water. The organic phase was washed with water (3 times),dried over MgSO₄ and concentrated. The residue was chromatographed oversilica gel using CHCl3/EtOH/aqueous NH3 (85/14/1) as eluant to give aN-benzyl piperazine derivative. This product in 30 mL of ethanol washydrogenated over 20% Pd(OH)2 on carbon at 60 psi hydrogen atmospherefor 18.4 h. The mixture was filtered and the filtrate concentrated. Theresidue (Sample A) was heated to reflux with toluene (4 mL) andtrimethylsilylisocyanate (2.5 mL) for 3 h. The mixture was cooled andchromatographed over silica gel using CHCl3/EtOH/aqueous NH3 (85/14/1)as eluant to give the title product as a white solid.

Anal. for C₂₁ H₂₅ N₃ O₂.0.5 H₂ O

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        69.98            C     69.78                                                  7.27             H     6.82                                                   11.66            N     11.53                                                  ______________________________________                                    

EXAMPLE 338A, B AND C ##STR496##

To a stirred solution of 1.5 g of tosylate prepared in example 186 in 20ml of N,N-dimethylformamide was added 1.5 g of K₂ CO₃ and 480 mg of4-azabenzimidazole. The mixture was heated to 65° C. for 4 hours, themixture was cooled to room temperature and extracted with ethyl acetate.The organic extract was washed with water, dried over Na₂ SO₄ andconcentrated in vacuo to give crude oily gum which was chromatographedover silica gel to yield the title compounds 338A, 338B and 338C (inorder of elution).

A: Calcd for C₂₁ H₁₉ N₃ O.1/2H₂ O: Calculated: C, 74.53; H, 5.96; N,12.42 Found: C, 74.30; H, 5.81; N, 12.45

B: Calcd for C₂₁ H₁₉ N₃ O: Calculated: C, 76.57; H, 5.89; N, 12.76Found: C, 76.48; H, 5.76; N, 12.81

C: Calcd for C₂₁ H₁₉ N₃ O.1/4H₂ O: Calculated: C, 75.54; H, 5.89; N,12.59 Found: C, 75.80; H, 5.75; N, 12.64

    TABLE 19                                                                         -                                                                              ##STR497##                                                                     Starting Tosylate                                                               or Starting   Isolation                                                       Ex. # Chloride ZH Product Chromatography Analysis                              339 Ex. 186                                                                    ##STR498##                                                                     ##STR499##                                                                     Silica, chloroform/ethanol/NH.sub.4 OH;92.5/7/0.5 C.sub.22 H.sub.20           H.sub.2 O:Calc: C, 80.46; H, 6.14; N, 8.53Found: C, 79.90; H, 6.23; N,         8.40                                                                           340 Ex. 186                                                                     ##STR500##                                                                     ##STR501##                                                                     Silica, ethanol/methylene chloride;10/90 C.sub.21 H.sub.19 N.sub.3            O.H.sub.2 O:Calc: C, 72.60; H, 6.09; N, 12.10Found: C, 72.94; H, 5.68;         N, 12.25                                                                        ##STR502##                                                                      C.sub.21 H.sub.18 N.sub.3 O.O.2H.sub.2 O:Calc: C, 75.74; H, 5.87; N,         12.62Found: C, 76.03; H, 5.90; N, 12.66                                         ##STR503##                                                                      C.sub.21 H.sub.19 N.sub.3 O.1/4H.sub.2 O:Calc: C, 75.54, H, 5.89; N,         12.59Found: C, 75.90; H, 5.92; N, 12.60                                        341 Ex. 216                                                                     ##STR504##                                                                     ##STR505##                                                                     Silica, methylenechloride/ethanol/NH.sub.4 OH;90/9/1 C.sub.22 H.sub.21        N.sub.3 O:Calc: C, 76.94; H, 6.16; N, 12.24Found: C, 76.78; H, 6.35; N,        12.20                                                                           ##STR506##                                                                      C.sub.22 H.sub.21 N.sub.3 O:Calc: C, 76.94; H, 6.16; N, 12.24Found: C,       76.58; H, 6.37; N, 12.14                                                       342 Ex. 186                                                                     ##STR507##                                                                     ##STR508##                                                                     Silica, 75/25;ethylacetate/toluene C.sub.22 H.sub.20 N.sub.2                   O.O.4H.sub.2 O:Calc: C, 78.73; H, 6.25; N, 8.35Found: C, 78.81; H,            6.33; N, 8.04                                                                  343 Ex. 184                                                                     ##STR509##                                                                     ##STR510##                                                                     Silica, methanol/methylene chloride/ammonium hydroxide1/98.5/0.5              C.sub.22 H.sub.20 N.sub.2 O.sub.2.0.25H.sub.2 O:Calc: C, 75.73; H, 5.92;       N, 8.03.Found: C, 75.72; H, 5.95; N, 7.96.                                     344 Ex. 188                                                                     ##STR511##                                                                     ##STR512##                                                                     silica gel, methanol/methylene chloride/ammonium hydroxide5/94/1              C.sub.21 H.sub.18 N.sub.2 O.sub.2.0.15H.sub.2 O:Calc: C, 75.73; H, 5.54;       N, 8.42.Found: C, 75.77:H, 5.62; N, 8.46.                                      345 Ex. 189                                                                     ##STR513##                                                                     ##STR514##                                                                     silica gel, methanol/methylene chloride/ammonium hydroxide1/98.5/0.5.         C.sub.22 H.sub.20 N.sub.2 O.sub.2                                               :Calc: C, 76.72; H, 5.85: N, 8.13.Found: C, 76.44; H, 5.98; N, 8.05.          346 Ex. 189                                                                     ##STR515##                                                                     ##STR516##                                                                     silica gel, methanol/methylene chloride/ammonium hydroxide1/98.5/0.5          C.sub.21 H.sub.19 N.sub.3 O.sub.2.0.2H.sub.2 O:Calc: C, 72.27; H, 5.60:        N, 12.04.Found: C, 72.34; H, 5.58; N, 11.54.H.R.M.S. M.sup.+  calc:            345.1477.Found: 345.1473.                                                       ##STR517##                                                                      C.sub.21 H.sub.19 N.sub.3 O.sub.2 :Calc: C, 73.03; H, 5.54; N,               12.17.Found: C, 73.12; H, 5.59; N, 12.15.                                       ##STR518##                                                                      C.sub.21 H.sub.19 N.sub.3 O.sub.2.020H.sub.2 O:Calc: C, 72.26; H,            5.60; N, 12.04.Found: C, 72.30; H, 5.62; N, 11.77.                             347 Ex. 189                                                                     ##STR519##                                                                     ##STR520##                                                                     methanol/methylenechloride/ammoniumhydroxide 1/98.5/0.5. C.sub.21             H.sub.19 N.sub.3 O.sub.2.040H.sub.2 O:Calc: C, 71.53; H, 5.66; N,              11.92.Found: C, 71.71; H, 5.66; N, 11.42.H.R.M.S. M.sup.+  calc:               345.1477.Found: 345.1479.                                                       ##STR521##                                                                      C.sub.21 H.sub.19 N.sub.3 O.sub.2.040H.sub.2 O:Calc: C, 71.53; H,            5.66; N, 11.92.Found: C, 71.21; H, 5.29; N, 11.57.                              ##STR522##                                                                      C.sub.21 H.sub.18 N.sub.3 O.sub.2.070H.sub.2 O:Calc: C, 70.45; H,            5.74: N, 11.74.Found: C, 70.58; H, 5.44; N, 11.41.                             348 Ex. 188                                                                     ##STR523##                                                                     ##STR524##                                                                     methanol/methylenechloride/ammoniumhydroxide 5/94/1 C.sub.20 H.sub.17         N.sub.3 O.sub.2.0.25H.sub.2 O:Calc: C, 71.52; H, 5.25; N, 12.51.Found:         C, 71.43; H, 5.17; N, 12.50.                                                    ##STR525##                                                                      C.sub.20 H.sub.17 N.sub.3 O.sub.2.050H.sub.2 O:Calc: C, 70.57; H,            5.33; N, 12.34.Found: C, 70.68; H, 5.34; N, 12.38.                              ##STR526##                                                                      H.R.M.S. M.sup.+                                                              calc: 331.1321.Found: 331.1296.                                                                  349 Ex. 188                                                  ##STR527##                                                                     ##STR528##                                                                     methanol/methylenechloride/ammoniumhydroxide 1/98.5/0.5. C.sub.20             H.sub.17 N.sub.3 O.sub.2 :Calc: C, 72.49; H, 5.17: N, 12.68.Found: C,          72.19: H, 5.23; N, 12.61.                                                       ##STR529##                                                                      C.sub.20 H.sub.17 N.sub.3 O.sub.2.0.15H.sub.2 O:Calc: C, 71.91; H,           5.22: N, 12.58.Found: C, 71.87; H, 5.22: N, 12.41.                              ##STR530##                                                                      C.sub.20 H.sub.17 N.sub.3 O.sub.2.1.75H.sub.2 O:Calc: C, 66.19; H,           5.69: N, 11.58.Found: C, 66.00; H, 5.29; N, 11.68                              350 Ex. 184                                                                     ##STR531##                                                                     ##STR532##                                                                     methanol/methylenechloride/ammoniumhydroxide 5/94/1. C.sub.21 H.sub.18        N.sub.3 O.sub.2.0.15H.sub.2 O:Calc: C, 72.46; H, 5.59; N, 12.07.Found:         C, 72.48; H, 5.65: N, 11.97.                                                    ##STR533##                                                                      C.sub.21 H.sub.19 N.sub.3 O.sub.2.0.50H.sub.2 O:Calc: C, 71.17; H,           5.69; N, 11.86.Found: C, 71.15; H, 5.26; N, 11.54.                              ##STR534##                                                                      H.R.M.S. M.sup.+                                                              calc: 345.1478.Found: 345.1493.                                                                  350 Ex. 184                                                  ##STR535##                                                                     ##STR536##                                                                     methanol/methylenechloride/ammoniumhydroxide 5/94/1. C.sub.21 H.sub.19        N.sub.3 O.sub.2.0.50H.sub.2 O:Calc: C, 71.17; H, 5.69; N, 11.86.Found:         C, 71.16; H, 5.46; N, 11.46.                                                    ##STR537##                                                                      C.sub.21 H.sub.19 N.sub.3 O.sub.2.050H.sub.2 O:Calc: C, 71.17; H,            5.69; N, 11.86.Found: C, 71.14: H, 5.39; N, 11.94.                              ##STR538##                                                                      C.sub.21 H.sub.18 N.sub.3 O.sub.2.050H.sub.2 O:Calc: C, 71.17; H,            5.69; N, 11.86.Found: C, 71.25; H, 5.42; N, 11.61.                             352 Ex. 186                                                                     ##STR539##                                                                     ##STR540##                                                                     Silica, chloroform/ethanol/NH.sub.4 OH;92.5/7/0.5 C.sub.18 H.sub.18           N.sub.2 O.HClCalc: C, 68.67; H, 6.08; N, 8.9.Found: C, 68.54; H, 6.07;         N, 8.79.                                                                       353 Ex. 186                                                                     ##STR541##                                                                     ##STR542##                                                                     Silica, EtOAc C.sub.22 H.sub.22 N.sub.4 O.sub.3 :Calc: C, 67.35; H,           5.84; N, 14.35.Found: C, 67.68; H, 5.68; N, 14.35.                             354 Ex. 161                                                                     ##STR543##                                                                     ##STR544##                                                                     100:1:1CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH C.sub.20 H.sub.18 FN.sub.3         O.sub.2 :Calc: C, 68.76; H.4.62; N, 12.03.Found: C, 68.66; H, 4.63; N,         11.78.                                                                          ##STR545##                                                                      C.sub.20 H.sub.18 FN.sub.3 O.sub.2 :Calc: C, 68.76; H.4.62; N,               12.03.Found: C, 68.40; H, 4.70; N, 11.86.                                       ##STR546##                                                                      HRMS, m/z 349.1222calc: C.sub.20 H.sub.16 FN.sub.3 O.sub.2, 349.1227.          355 Ex. 161                                                                   ##STR547##                                                                     ##STR548##                                                                     100:1:1CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH C.sub.20 H.sub.18 FN.sub.3         O.sub.2.0.2H.sub.2 O:Calc: C, 68.06; H, 4.68; N, 11.90.Found: C, 68.28;        H, 4.72; N, 11.72.                                                              ##STR549##                                                                      HRMS, m/z 349.1244calc: C.sub.20 H.sub.16 FN.sub.3 O.sub.2, 349.1227.         ##STR550##                                                                      mp 126-128°                                                            C.                                                                                                356 Ex. 216                                                 ##STR551##                                                                     ##STR552##                                                                     silica gel, methanol/methylene chloride/ammonium hydroxide5/94.5/0.5.         C.sub.22 H.sub.21 N.sub.3 O.0.1H.sub.2 O:Calc: C, 76.54; H, 6.19; N,           12.17.Found: C, 76.86; H, 6.15; N, 12.10.                                       ##STR553##                                                                      C.sub.22 H.sub.21 N.sub.3 O0.2H.sub.2 O:Calc: C,.76.14;.H, 6.22; N,          12.11.Found: C, 76.05; H, 6.30; N, 11.97.                                       ##STR554##                                                                      C.sub.22 H.sub.21 N.sub.3 O.0.1H.sub.2 O:Calc: C, 76.54; H, 6.19; N,         12.17.Found: C, 76.32; H, 6.35; N, 12.21.                                      357 Ex. 186                                                                     ##STR555##                                                                     ##STR556##                                                                     silica gel, methanol/methylene chloride/ammonium hydroxide5/94.5/0.5.         C.sub.20 H.sub.18 N.sub.4 O0.1H.sub.2 O:Calc: C, 72.31; H, 5.52; N,            16.87.Found: C, 72.22; H, 5.59; N, 16.90.                                       ##STR557##                                                                      C.sub.20 H.sub.18 N.sub.4 O0.1H.sub.2 O:Calc: C, 72.31; H, 5.52; N,          16.87.Found: C, 72.18; H, 5.53; N, 16.83.                                       ##STR558##                                                                      C.sub.20 H.sub.18 N.sub.4 O0.5H.sub.2 O:Calc: C, 70.78; H, 5.64; N,          16.51.Found: C, 70.61; H, 5.44; N, 16.52.                                       ##STR559##                                                                      C.sub.20 H.sub.18 N.sub.4 0.1HCl, 1.3H.sub.2 O:Calc: C, 61.55; H,            5.58; N, 14.36.Found: C, 61.24; H, 5.18; N, 15.03.                             358 Ex. 180                                                                     ##STR560##                                                                     ##STR561##                                                                     Ethanol/methylenechloride/aq. NH.sub.3 10/90/1 C.sub.22 H.sub.18              N.sub.3 O.2HCl.Calc: C, 63.77; H, 5.11; N, 10.14; Cl, 17.11.Found: C,          63.43; H, 5.32; N, 10.11; Cl, 16.95.                                            ##STR562##                                                                      C.sub.22 H.sub.18 N.sub.3 O.1.5HCl.0.5H.sub.2 OCalc: C, 65.23; H,            5.35; N, 10.37; Cl, 13.13.Found: C, 64.95; H, 5.32; N, 10.37; Cl, 13.50.        ##STR563##                                                                      C.sub.22 H.sub.19 N.sub.3 O.19HCl.0.25H.sub.2 OCalc: C, 62.29; H,            5.32; N, 9.91; Cl, 15.88.Found: C, 62.66; H, 5.33; N, 10.05; Cl, 15.88.        359 Ex. 180                                                                     ##STR564##                                                                     ##STR565##                                                                     Ethanol/methylenechloride/aq. NH.sub.3 10/90/1 C.sub.22 H.sub.19              N.sub.3 O.HCl.0.25H.sub.2 OCalc: C, 69.10; H, 5.40; N, 10.99; Cl,              9.27.Found: C, 69.11; H, 5.50; N, 11.48; Cl, 9.48.                              ##STR566##                                                                      C.sub.22 H.sub.18 N.sub.3 O.0.5H.sub.2 OCalc: C, 75.41; H, 5.75; N,          11.99.Found: C, 74.92; H, 5.61; N, 11.95.                                       ##STR567##                                                                      C.sub.22 H.sub.19 N.sub.3 O.1.05HCl.0.5H.sub.2 OCalc: C, 67.98; H,           5.45; N, 10.81; Cl, 9.58.Found: C, 67.46; H, 5.48; N, 10.51; Cl, 9.57.         360 Ex. 180                                                                     ##STR568##                                                                     ##STR569##                                                                     Ethylacetate/toluenelinear gradient 5/95 to11/89 C.sub.21 H.sub.18            N.sub.4 O.0.05H.sub.2 OCalc: C, 73.47; H, 5.31; N, 1 6.32.Found: C,            73.07; H, 5.40; N, 16.01.                                                       ##STR570##                                                                      C.sub.21 H.sub.18 N.sub.4 OCalc: C, 73.67; H, 5.30; N, 16.36.Found: C,       73.58; H, 5.38; N; 16.32.                                                       ##STR571##                                                                      C.sub.21 H.sub.18 N.sub.4 OCalc: C, 73.67; H, 5.30; N, 16.36.Found: C,       73.77; H, 5.45; N, 16:30.                                                      361 Ex. 180                                                                     ##STR572##                                                                     ##STR573##                                                                     Ethanol/methylenechloride/aq. NH.sub.3 10/90/1 C.sub.21 H.sub.18              N.sub.4 O.HClCalc: C, 66.58; H, 5.06; N, 14.79; Cl, 9.36.Found: C,             66.39; H, 5.04; N, 14.73; Cl, 9.32.                                             ##STR574##                                                                      C.sub.21 H.sub.18 N.sub.4 O.0.25H.sub.2 OCalc: C, 72.72; H, 5.38; N,         16.15.Found: C, 73.00; H, 5.49; N, 16.36.                                 

EXAMPLE 362A AND B ##STR575##

To a stirred solution of 764 mg of the tosylate prepared according toexample 186 in 10 ml of DMF was placed 1 g of K₂ CO₃ and 326 mg of5-nitrobenzimidazole. The reaction mixture was heated to 65° C. and wasstirred at 65° C. under nitrogen atmosphere for 4 hours. The reactionmixture was cooled to room temperature, poured into water and extractedwith ethyl acetate. The organic extract was washed with water, driedover Na₂ SO₄ and concentrated in vacuo to afford a residue which wastaken up in 8 ml of 1:1 mixture of ethanol and HCl. The mixture wastreated with 800 mg of SnCl₂.2H₂ O in 1 ml of concentrated HCl. Themixture was heated on the steam bath for 45 minutes, cooled to roomtemperature and neutralized 10% NaOH solution. The basic solution wasextracted with ethyl acetate. The organic extract was washed with water,dried over Na₂ SO₄, concentrated in vacuo to yield an oily residue whichwas chromatographed on silica gel using 92.5% CHCl₃, 7% ethanol, and0.5% NH₄ OH as eluant to provide the title compounds.

A: Calcd for C₂₂ N₂₁ N₃ O₁.1/4H₂ O: Calc: C, 75.91; H, 6.23; N, 12.08Found: C, 75.96; H, 6.10; N, 12.03

B: Calcd for C₂₂ H₂₁ N₃ O.1/4H₂ O: Calc: C, 75.95; H, 6.23; N, 12.08Found: C, 75.73; H, 6.05; N, 11.94

EXAMPLE 363 ##STR576##

To a stirred solution of 200 mg of the compound prepared in example 338Bin 5 ml of CHCl₃ was added 200 mg of 80-85% m-chloroperoxybenzoic acidand the mixture was stirred at room temperature for 1 hr. The mixturewas diluted with 10 ml of CHCl₃ and was washed with 10% K₂ CO₃ solutionand water, dried over Na₂ SO₄ and concentrated. The residue waschromatographed over silica gel using 85% CHCl₃, 14% ethanol and 1%aqueous NaOH as eluant to yield the title compound as white solid(example 49).

Calcd for C₂₁ H₁₉ N₃ O₂.1/4H₂ O: Calc: C, 72.09: H, 5.62; N, 12.01Found: C, 71.71; H, 5.50; N, 11.81

EXAMPLE 364 ##STR577##

Following the procedure described in example 363 and replacing thecompound of example 338B with the compound of example 340C provided thetitle compound as white solid.

Calcd for C₂₁ H₁₉ N₃ O2.1/4H₂ O: Calc: C, 72.09; H, 5.02; N, 12.01Found: C, 72.16; H, 5.62; N, 11.96

EXAMPLE 365 ##STR578##

Following the procedure described in example 363 and replacing thecompound of example 338B with the compound of example 340B provided thetitle compound as white solid.

Calcd for C₂₁ H₁₉ N₃ O₂.1/4H₂ O: Calc: C, 72.09; H, 5.62; N, 12.01Found: C, 72.31; H, 5.82; N, 12.05

EXAMPLE 366 ##STR579##

To stirred ethylene glycol (200 mn) was added sodium pellets (5.75 g,250 mmol, Aldrich). After the sodium was dissolved the solution wascooled to room temperature. To this solution was added copper (II) oxide(4.8 g, 60 mmol), and 2-iodothiophene (25 g, 119 mmol). This mixture wasthen heated at 120° C. for 40 hours. The mixture was cooled to roomtemperature and poured into water (1000 mL). The aqueous mixture wasthen extracted with two 250 mL portions of ether. The combined etherextracts were washed 3 times with water (2×100 mL), saturated brine (100mL) and dried over MgSO₄. After filtration, the volatile components wereremoved at reduced pressure on a rotary evaporator. The residue waschromatographed on silica gel gradient eluting with ethyl acetate:hexane(100% hexane to 1:5). This produced 15.9 g (30.3%) of the title compoundas an oil.

HRMS (M+) for C₆ H₈ O₂ S Calculated: 144.0245 Found: 144.0245

EXAMPLE 367 ##STR580##

To a stirred solution of the product of Example 366 (1 g, 7 mmol) intetrahydrofuran (20 mL) at -50° C. was added n-butyllithium (1.6M inTHF, 10 mL, 16 mmol) dropwise over one minute. The mixture was slowlywarmed over one hour to -20° C. and then cooled to -50° C. The mixturewas then treated with benzyl bromide (0.9 mL, 7.6 mmol) and warmed toroom temperature over one hour. The mixture was poured into water (50mL), saturated brine (25 mL) and dried over MgSO4. After filtration, thevolatile components were removed at reduced pressure on a rotaryevaporator. The crude product was used in Example 368 without furtherpurification.

EXAMPLE 368 ##STR581##

To a cooled (0° C.) and stirred solution of the product of Example 367(1.6 g, 7 mmol) in methylene chloride (25 mL) was added pyridine (2.2mL, 28 mmol) and p-toluenesulfonyl chloride (2.7 g, 14 mmol). Themixture was allowed to warm to room temperature and stirred for 18hours. The mixture was poured into water (100 mL) and extracted with two50 mL portions of ethyl acetate. The combined ethyl acetate extractswere washed 2 times with water (2×25 mL), saturated brine (25 mL) anddried over MgSO₄. After filtration, the volatile components were removedat reduced pressure on a rotary evaporator. The residue waschromatographed on a reverse phase column gradient eluting withmethanol-water. This produced 0.64 g (24%) of the title compound.

HRMS (M+) for C₂₀ H₂₀ S₂ O₄ Calculated: 388.0803 Found: 388.0803

EXAMPLE 369 ##STR582##

To a stirred solution of the product of Example 368 (0.1 g, 0.26 mmol)and isonipecotamide (0.06 g, 0.5 mmol, Aldrich) in N,N-dimethylformamide(5 mL) was added anhydrous potassium carbonate (0.25 g) in one portion.This mixture was heated at 80° C. for 18 hours. The mixture was pouredinto water (100 mL) and extracted with 25 mL of ethyl acetate. The ethylacetate was washed 2 times with water (2×25 mL), saturated brine (25 mL)and dried over MgSO₄. After filtration, the volatile components wereremoved at reduced pressure on a rotary evaporator. The residue waschromatographed on silica gel gradient eluting with hexane:ethyl acetate(1:1 to 100% ethyl acetate) saturated with aqueous concentrated ammoniumhydroxide. The solid produced was triturated with ether. This produced0.02 g (22.3%) of the title compound.

HRMS (M+) for C₁₉ H₂₄ N₂ SO₂ : Calculated: 344.1558 Found: 344.1566.

EXAMPLE 370 ##STR583##

The product from Example 368 (0.1 g, 0.26 mmol) and ethyl isonipecotate(0.08 g, 0.5 mmol, Aldrich) was subjected to the reaction conditionsdescribed for the preparation of Example 369. The crude product waschromatographed on silica gel eluting with ethyl acetate:hexane (1:1)saturated with aqueous concentrated ammonium hydroxide. The product wastaken up in ether (5 mL) and treated with hydrogen chloride and theresulting solid was triturated with ether. This produced 0.06 g (56%) ofthe title compound.

HRMS (M+) for C₂₁ H₂₇ NO₃ S: Calculated: 373.1712 Found: 373.1715

EXAMPLE 371 ##STR584##

To a stirred solution of the product of Example 370 (0.04 g, 0.1 mmol)in tetrahydrofuran (2 mL) was added 6N HCl (5 drops). This solution washeated at 60° C. for 5 hours. The volatile components were removed atreduced pressure on a rotary evaporator and the residue was trituratedwith ether to give the title compound.

HRMS (MH+) for C₁₉ H₂₃ NO₃ S: Calculated: 346.1477 Found: 346.1479.

EXAMPLE 372 ##STR585##

1,3-Propanediol (200 mL, Aldrich) was subjected to the reactionconditions described for the preparation of Example 366. This produced13.2 g (70%) of the title compound.

HRMS (M+) for C₇ H₁₀ O₂ S: Calculated: 158.0402 Found: 158.0397.

EXAMPLE 373 ##STR586##

The product from Example 372 (6 g, 37.9 mmol) was subjected to thereaction conditions described for the preparation of Example 362. Theresidue was chromatographed on a reverse phase column gradient elutingwith methanol-water. This produced 0.76 g (7.9%) of the title compound.

HRMS (M+) for C₁₄ H₁₆ O₂ S: Calculated: 248.0871 Found: 248.0874.

EXAMPLE 374 ##STR587##

The product from Example 373 (0.5 g, 2.01 mmol) was subjected to thereaction conditions described for the preparation of Example 368. Thecrude product was chromatographed on silica gel gradient eluting withethyl acetate:hexane (1:19 to 1:9). This produced 0.53 g (65%) of thetitle compound.

NMR (CDCl₃): 7.76 (d, 2H), 7.35-7.19 (complex, 7H), 6.37 (d, 1H), 5.90(d, 1H), 4.16 (T, 2H), 3.98 (S, 2H), 3.95 (T, 2H), 2.39 (S, 3H), 2.06(Pent., 2H).

EXAMPLE 375 ##STR588##

The product from Example 374 (0.2 g, 0.5 mmol) and N-methyl-β-alaninewas subjected to the reaction conditions described for the preparationof Example 369. The crude product was chromatographed on silica geleluting with ethyl acetate:hexane (1:4). The product was taken up inether (5 mL) and treated with hydrogen chloride and the resulting solidwas triturated with ether. This produced 0.08 g (42%) of the titlecompound.

HRMS (MH+) for C₁₉ H₂₅ SNO₃ : Calculated: 348.1633 Found: 348.1651.

EXAMPLE 376 ##STR589##

To a stirred suspension of sodium hydride (prewashed with hexane)(3.2 g,50% oil dispersion) in DMF (100 ml) 4-hydroxydiphenylmethane (10 g, 54mmol) was added. The reaction mixture stirred at room temperature for 30minutes, cooled to 0° C. and tetra-n-butylammonium iodide (cat) followedby tert butylbromo acetate (9.6 ml, 1.1 eq) were added. After 30 minutesthe reaction mixture was quenched into a mixture of 2N hydrochloricacid/ice and the resulting solution extracted into diethyl ether. Theorganic extracts were separated, washed with saturated potassiumhydrogen sulfate, followed by saturated potassium carbonate, dried (Na₂SO₄) and evaporated to afford the title compound as a yellow oil.

The resulting yellow oil was further purified by chromatography onsilica (eluant: diethyl ether/hexane 10/90) to afford the title compoundas a colorless oil (15.02 g). NMR spectrum of this oil was consistentwith the proposed structure.

EXAMPLE 377 ##STR590##

To a stirred solution of the t-butyl ester from example 376 (2.78 g, 10mmol) in THF(100 ml) at -78° C., lithium diisopropylamide (6 ml, 2Msolution (Aldrich), 1.2 eq) was added. The reaction mixture was stirredat -78° C. for 40 min, quenched with methyl iodide (1 ml, excess) andallowed to attain room temperature. The reaction mixture was evaporated,and partitioned between diethyl ether and saturated potassium hydrogensulfate solution. The organic extracts were separated, dried (Na₂ SO₄)and evaporated to afford a yellow oil (3.2 g). The crude product waspurified by chromatography on silica (eluant; hexane/diethyl ether,80/20) to afford the title compound (2.76 g,).

This compound was characterized by NMR and fully authenticated at thenext step (Example 381).

                                      TABLE 20                                    __________________________________________________________________________    Ex. No.                                                                           Compound                 Alkylating Agent                                                                      Analysis                                 __________________________________________________________________________    378                                                                                ##STR591##              EtI     C.sub.21 H.sub.26 O.sub.3 : Calc: C,                                          77.27; H, 8.03. Found: C, 76.95; H,                                           8.32.                                    379                                                                                ##STR592##              BnBr    C.sub.26 H.sub.26 O.sub.3 : Calc: C,                                          79.46; H, 7.31. Found: C, 79.31; H,                                           7.32.                                    __________________________________________________________________________

EXAMPLE 380 ##STR593##

To a stirred solution of t-butyl ester from example 376 (9.60 g, 34.5mmol) in methylene chloride (50 ml) and methanol (5 ml) at 0° C.trifluoroacetic acid (50 ml, prechilled in ice) was added. The reactionmixture was stirred at 0° C. for 20 minutes, then allowed to attain roomtemperature overnight. The reaction mixture was evaporated to afford anoff white solid which was recrystallized from diethyl ether/hexane toyield the title compound (6.12 g).

Analysis Calculated for C₁₅ H₁₄ O₃ 0.1 H₂ O: Calculated: C, 73.82; H,5.86. Found: C, 73.77; H, 5.76.

Following examples were carried out (i.e. examples 381, 382, 383) asdescribed in Example 380.

                                      TABLE 21                                    __________________________________________________________________________    Ex. No.                                                                           Compound                 Starting Ester                                                                       Analysis                                  __________________________________________________________________________    381                                                                                ##STR594##              Ex. 377                                                                              C.sub.16 H.sub.16 O.sub.3 : Calc: C,                                          73.69; H, 6.38. Found: C, 73.83; H,                                           6.24.                                     382                                                                                ##STR595##              Ex. 378                                                                              C.sub.17 H.sub.18 O.sub.3 : Calc: C,                                          74.30; H, 6.78. Found: C, 74.21; H,                                           6.69.                                     383                                                                                ##STR596##              Ex. 379                                                                              C.sub.22 H.sub.20 O.sub.3 0.6H.sub.2                                          O: Calc: C, 78.99; H, 6.23. Found: C,                                         76.90; H, 5.88.                           __________________________________________________________________________

EXAMPLE 384 ##STR597##

To a stirred solution of the acid from example 380 (800 mg, 3.31 mmol)in dimethylformamide (10 ml) and pyridine (2 ml), disuccinyl carbonate(842 mg) and 4-dimethylaminopyridine (cat) were added. The reactionmixture was stirred at room temperature for 50 minutes and thenD-prolinol (500 mg) was added. The reaction mixture was stirredovernight, evaporated, and partitioned between ethyl acetate andsaturated potassium hydrogen sulfate solution. The organic extracts wereseparated, dried (Na₂ SO₄) and evaporated to afford an off white solid(crude yield=1.20 g). The crude solid was dissolved in acetic anhydride,to which pyridine (2-drops) were added. The reaction mixture was stirredfor 4 hours, quenched with saturated sodium hydrogen carbonate solutionand extracted into ethyl acetate. The organic extracts were separated,dried (Na₂ SO₄) and evaporated to afford an off white solid. This crudeproduct was further purified by chromatography on silica (eluant;diethyl ether) to afford the title compound (920 mg).

Analysis calculated for C₂₂ H₂₅ NO₄ 0.15 H₂ O: Calc: C, 71.39; H, 6.89;N, 3.78. Found: C, 71.37; H, 6.82; N, 3.70.

EXAMPLE 385 ##STR598##

The title compound was prepared from the amide described in example 384(650 mg) in a manner identical to that described in example 397. Thisafforded the title compound (360 mg).

Analysis calculated for C₂₀ H₂₅ NO₂.1 HCl.0.8 H₂ O: Calc: C, 66.30; H,7.68; N, 3.87. Found: C, 66.13; H, 7.71; N, 4.21.

EXAMPLE 386 ##STR599##

The title compound was prepared as described in examples 384 and 385above, replacing D-prolinol with 3-hydroxy pyrrolidine, to afford thetitle compound (100 mg).

Analysis Calculated for C₁₉ H₂₃ NO₂.1 HCl.0.5 H₂ O: Calc: C, 66.56; H,7.35; N, 4.09. Found: C, 66.42; H, 7.06; N, 4.53.

EXAMPLE 387 1-(1-piperidinyl)-2- 4-(phenylmethyl)phenoxy!ethanone##STR600##

245 mg of sodium hydride (50% in oil) washed with hexane to remove theoil, was added to the solution of 920 mg of 4-hydroxydiphenylmethane in10 ml of N,N-dimethylformamide. The mixture was stirred at roomtemperature under nitrogen atmosphere for 10 minutes, and then 806 mg of1-(chloroacetyl)piperidine was added to the mixture. The reactionmixture was poured into water and was extracted with ether. The etherextract was washed with water, followed by 10% NaOH solution, dried overNa₂ SO₄. The solvent was removed by evaporation under reduced pressureto provide crude product which was crystallized from ether/hexane toprovide 656 mg of the title compound as white crystalline solid.

Analysis calculated for C₂₀ H₂₃ NO₂ : Calc: C, 77.64; H, 7.49; N, 4.53.Found: C, 77.83; H, 7.49; N, 4.49.

EXAMPLE 388 1-(2,6-dimethylpiperidin-1-yl)-2-4-(phenylmethyl)phenoxy!ethanone ##STR601##

Following the procedure described in example 387 and replacing1-(chloroacetyl)piperidine with 1-(chloroacetyl)-2,6-dimethylpiperidineyielded the title compound.

Analysis calculated for C₂₂ H₂₇ N₂ O.0.1H₂ O: Calc: C, 77.89; H, 8.08,N, 4.13. Found: C, 77.84, H, 8.16; N, 4.13.

EXAMPLE 389 ##STR602##

To stirred solution of the acid from example 380 (800 mg, 3.31 mmol) indimethylformamide (10 ml) and pyridine (2 ml), disuccinyl carbonate (842mg) and 4-dimethylaminopyridine (cat) were added. The reaction mixturewas stirred at room temperature for 50 minutes and thenhexamethyleneimine (330 mg) was added. The reaction mixture was stirredovernight, evaporated, and partitioned between ethyl acetate andsaturated potassium hydrogen sulfate solution. The organic extracts wereseparated, dried (Na₂ SO₄) and evaporated to afford an off white solid(crude yield=1.1 g). The crude product was purified by chromatography onsilica (eluant; diethyl ether/hexane, 70/30) to afford the titlecompound (800 mg).

Analysis calculated for C₂₁ H₂₅ NO₂ 0.15 H₂ O: Calc: C, 77.34; H, 7.82;N, 4.29. Found: C, 77.40; H, 7.84; N, 4.30.

                                      TABLE 22                                    __________________________________________________________________________    Ex. No.                                                                           Compound                    Starting Amine and Acid                                                                   Analysis                          __________________________________________________________________________    390                                                                                ##STR603##                 Azacycloheptane and Ex.                                                                   C.sub.22 H.sub.27 NO.sub.2 :                                                  Calc: C, 78.30; H, 8.06; N,                                                   4.15. Found: C, 78.15; H,                                                     7.85; N, 4.12.                    391                                                                                ##STR604##                 2,5 Dimethyl pyrrolldine and Ex.                                                          C.sub.21 H.sub.25 NO.sub.2                                                    0.1H.sub.2 O: Calc: C, 77.50;                                                 H, 7.81; N, 4.31. Found: C,                                                   77.48; H, 7.83; N, 4.36.          392                                                                                ##STR605##                 S-(+)-2-(methoxymethyl)- pyrrolidine and                                      Ex. 380     NMR spectrum was consistent                                                   with the proposed structure.                                                  Compound was fully                                                            characterized in the next                                                     step. See Example No. 400.        393                                                                                ##STR606##                 piperidine and Ex. 381                                                                    C.sub.21 H.sub.25 NO.sub.2                                                    0.1H.sub.2 O: Calc: C, 77.55;                                                 H, 7.81; N, 4.31. Found: C,                                                   77.56; H, 7.79; N, 4.36.          394                                                                                ##STR607##                 hexahydroazepine and Ex.                                                                  Compound was fully                                                            characterized in the next                                                     step. See Example No. 397.        395                                                                                ##STR608##                 pyrrolidine and Ex. 382                                                                   C.sub.20 H.sub.23 NO.sub.2.0.6                                                H.sub.2 O: Calc: C, 75,46; H,                                                 7.90; N, 4.19. Found: C,                                                      75.44; H, 8.14: N, 4.03.          396                                                                                ##STR609##                 pyrrolidine and Ex. 383                                                                   C.sub.26 H.sub.27 NO.sub.2.1.3                                                H.sub.2 O: Calc: C, 75.70; H,                                                 7.33; N, 3.40. Found: C,                                                      75.64; H, 7.02; N,                __________________________________________________________________________                                                3.24.                         

EXAMPLE 397 ##STR610##

To a stirred suspension of Lithium aluminum hydride (400 mg, excess) inTHF (10 ml) at room temperature, the amide for example 389 (700 mg) wasadded. The reaction mixture was stirred at room temperature for 3 hours,quenched with water (1 ml) and then diluted with ethyl acetate (50 ml).The reaction mixture was filtered and the mother liquors evaporated toafford a colorless oil. The free amine was converted to its HCl salt andcrystallized from ethanol/diethyl ether to afford the title compound(545 mg).

Analysis calculated for C₂₁ H₂₇ NO 1 HCl 0.2 H₂ O: Calc: C, 72.17; H,8.19; N, 4.01. Found: C, 72.21; H, 8.21; N, 4.07.

                                      TABLE 23                                    __________________________________________________________________________    Ex. No.                                                                           Compound                     Starting Material                                                                     Analysis                             __________________________________________________________________________    398                                                                                ##STR611##                  Ex. 390 C.sub.21 H.sub.29 NO.1HCl: Calc:                                              C, 73.41; H, 8.40; N, 3.89.                                                   Found: C, 73.04; H, 8.58; N,                                                  3.99.                                399                                                                                ##STR612##                  Ex. 391 Calcd for C.sub.21 H.sub.27                                                   NO.HCl: Calc: C, 72.92; H, 8.10;                                              N, 4.05. Found: C, 72.70; H,                                                  8.47; N, 3.99.                       400                                                                                ##STR613##                  Ex. 392 C.sub.21 H.sub.27 NO.sub.2                                                    HCl.1/2H.sub.2 O: Calc: C,                                                    68.00; H, 7.88; N, 3.78. Found:                                               C, 67.91; H, 7.75; N, 4.06.          401                                                                                ##STR614##                  Ex. 387 C.sub.20 H.sub.25 NO.HCl: Calc:                                               C, 72.38; H, 7.90; N, 4.22.                                                   Found: C, 72.23; H, 7.93; N,                                                  4.21.                                402                                                                                ##STR615##                  Ex. 388 C.sub.22 H.sub.29 NO.HCl: Calc:                                               C, 73.41; H, 8.40; N, 3.89.                                                   Found: C, 73.43; H, 8.49; N,                                                  3.59.                                403                                                                                ##STR616##                  Ex. 393 C.sub.20 H.sub.25 NO.1HCl0.2H.sub                                             .2 O: Calc: C, 72.17; H, 8.19;                                                N, 4.01. Found: C, 72.26; H,                                                  8.12; N, 4.10.                       404                                                                                ##STR617##                  Ex. 394 C.sub.22 H.sub.29 NO.1HCl0.15H.su                                             b.2 O: Calc: C, 72.87; H, 8.42;                                               N, 3.86. Found: C, 72.85; H,                                                  8.49; N, 4.00.                       405                                                                                ##STR618##                  Ex. 395 C.sub.21 H.sub.27 NO.1HCl0.2H.sub                                             .2 O: Calc: C, 72.17; H, 8.19;                                                N, 4.01. Found: C, 72.21; H,                                                  8.19; N, 3.96.                       406                                                                                ##STR619##                  Ex. 396 C.sub.26 H.sub.29 NO.1HCl0.1H.sub                                             .2 O: Calc: C, 76.21; H, 7.43;                                                N, 3.42. Found: C, 76.10; H,                                                  7.45; N, 3.31.                       __________________________________________________________________________

EXAMPLE 407 ##STR620##

1) 3-Bromo propionaldehyde dimethyl acetal was reacted with 4-hydroxydiphenyl methane as in example 216 and was purified through columnchromatography to afford intermediate A. ##STR621##

2) 1 g of intermediate A in 10 ml of THF was added 0.5 ml of H₂ O.P-toluenesulfonic acid 50 mg was added and heated to 70° overnight. Thesolvent was removed and the organic material was extracted with 30 mlether. The etherial extracts were dried (Na₂ SO₄) and evaporated toafford to intermediate aldehyde B. ##STR622##

3) The intermediate B 240 mg in 3 ml of EtOH was added 177 mg of ethyl3-amino pentyn-1-carboxylate (The NutraSweet Company) and 1 mmole of KOH(56 mg) and was stirred for 1/2 hr. 63 mg of NaBH₃ CN was then added andthe reaction was worked up as example 12 and after chromatography toprovide 20 mg of the title compound as a colorless oil.

Analysis for C₂₃ H₂₇ NO₃.0.1H₂ O

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             74.18   74.17                                                   H             7.36    7.66                                                    N             3.75    3.77                                                    ______________________________________                                    

EXAMPLE 408 ##STR623##

The title compound was prepared in accordance with example 407 exceptthat bromoacetaldehyde diethyl acetal was used instead of3-bromopropionaldehyde dimethyl acetal.

Analysis for C₂₂ H₂₅ NO₃

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             75.19   69.79                                                   H             7.17    7.11                                                    N             3.98    4.21                                                    ______________________________________                                    

EXAMPLE 409 ##STR624##

To a stirred solution 100 mg of the compound of example 261 in 5 ml DMFwas added NaH 12 mg (60% dispersion, Aldrich). After 10 minutes ofstirring, 30 mg benzyl bromide (Aldrich) in 2 ml DMF was added dropwisestirred at room temperature for 1 hr. Organic material was extractedwith 30 ml ether and was washed with H₂ O (5 ml×3), dried, and purifiedby column chromatography to provide 60 mg of the title compound as acolorless oil.

Analysis for C₂₉ H₃₃ NO₃

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             78.52   78.18                                                   H             7.50    7.50                                                    N             3.16    3.06                                                    ______________________________________                                    

EXAMPLE 410 Preparation of ethyl 4-4-(phenylmethyl)phenoxy!butyl!(2-propenyl)amino!propanoate ##STR625##

150 mg of the compound of example 271 was reacted in accordance with themethod of example 409 to provide mg of the title compound as a colorlessoil.

Analysis for C₂₅ H₃₃ NO₃

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             75.92   75.94                                                   H             8.41    8.59                                                    N             3.54    3.43                                                    ______________________________________                                    

EXAMPLE 411 ##STR626##

To 100 mg of the compound of example 261 and 0.1 ml of 37% aq HCHO in 2ml of CH₃ CN was added 25 mg of NaBH₃ CN and the reaction mixturestirred for 15 min. Two drops of glacial acetic acid was added and thereaction mixture was stirred for another 30 min. Solvent was removed invacuo and the remaining mixture was basified with 15% KOH to pH 8 andthe organic material was extracted with 20 ml ether. The organic phasewas washed with H₂ O (10 ml×3) and was dried. It was filtered and theresulting oily substance was purified by silica gel chromatography using50:50:1-EtOAc:tol:TEA as eluant to provide 90 mg of the title compound.

Analysis for C₂₅ H₂₇ NO₃.0.2H₂ O

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             76.39   76.10                                                   H             7.03    7.05                                                    N             3.56    3.48                                                    ______________________________________                                    

EXAMPLE 412 ##STR627##

170 mg of the compound of example 265 was converted to 100 mg of thetitle compound using the procedure described in example 411.

Analysis for C₂₂ H₂₉ NO₃

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             74.33   74.28                                                   H             8.22    8.44                                                    N             3.94    4.00                                                    ______________________________________                                    

EXAMPLE 413 ##STR628##

160 mg of the compound of example 267 was converted to 37.4 mg of thetitle compound following the procedure of example 411.

Analysis for C₂₁ H₂₇ NO₃.H₂ O

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             70.17   69.85                                                   H             8.13    8.04                                                    N             3.90    3.92                                                    ______________________________________                                    

EXAMPLE 414 ##STR629##

770 mg of the compound of example 265 was reacted with 3-pyridinecarboxaldehyde (Aldrich) 0.12 g following the procedure of example 411.Silica gel chromatography afforded 0.7 g of the title compound.

Analysis for C₂₇ H₃₂ N₂ O₃.0.2H₂ O

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             74.70   74.31                                                   H             7.06    7.49                                                    N             6.45    6.28                                                    ______________________________________                                    

EXAMPLE 415 ##STR630##

640 mg of the compound of example 272 was reacted in accordance with themethod described in example 411 to obtain 350 mg of the title compoundas a colorless oil.

Analysis for C₂₂ H₃₁ NO₃.0.4 Et₃ N.0.2H₂ O

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             73.76   73.43                                                   H             9.11    8.66                                                    N             4.74    4.33                                                    ______________________________________                                    

EXAMPLE 416 ##STR631##

The compound of example 265 (267 mg) in anhyd. THF was cooled to 0° C.and 2 mmol of MeMgCl in THF was added during 1/2 hr and stirred at roomtemperature for 1/2 hr. 2 ml of aqueous NH₄ Cl solution was addeddropwise at 0° C. and the solvent was removed in vacuo. The organicmaterial was extracted with 30 ml ether and was chromatographed in asilica gel column using 20:80:1-EtOH:EtOAc-TEA as eluant to provide 75mg of the title compound as a colorless oil.

Analysis for C₂₁ H₂₉ NO₂.0.5H₂ O

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             74.96   74.80                                                   H             8.99    8.35                                                    N             4.16    4.65                                                    ______________________________________                                    

EXAMPLE 417 ##STR632##

1.13 g of the compound of example 411 in THF was added dropwise to 3mmol of LDA in 20 ml of THF at -78° during 1/2 hr. After 1/2 hr at -78°,5 mmol of methyl iodide was added and reaction mixture was warmed toroom temperature. Solvent was removed in vacuo and organic material wasextracted with 50 ml ether and was dried. The desired product, 590 mg ofthe title compound, was obtained from column chromatography as colorlessoil.

Analysis for C₂₈ H₃₃ NO₃.0.2H₂ O

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             77.28   77.00                                                   H             7.74    7.86                                                    N             3.22    3.07                                                    ______________________________________                                    

EXAMPLE 418 ##STR633##

Product of example 417, (290 mg) was subjected to conditions describedin example 417 and after chromatography on silica gel, a colorless oilwas obtained, 21.4 mg.

Analysis for C₂₉ H₃₅ NO₃ EtOAc

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             74.27   74.54                                                   H             8.12    7.76                                                    N             2.62    2.66                                                    ______________________________________                                    

EXAMPLE 419 ##STR634##

To a stirred solution of 350 mg of the ester of example 245 in 3 ml ofn-butanol was added 1 g of hydrazine hydrate and the mixture was heatedto reflux and was allowed to reflux under nitrogen atmosphere for 6hours. The mixture was cooled to room temperature. The solvent wasremoved by evaporation under reduced pressure to give the crude oilygum, which upon crystallization from diethyl ether provided the titlecompound as white solid.

Calcd for C₂₁ H₂₇ N₃ C₂.0.2H₂ O: C, 70.64; H, 7.73; N, 11.77. Found: C,70.62; H, 7.88; N, 11.71.

EXAMPLE 420 ##STR635##

Following the procedure described in example 419 and replacing hydrazinehydrate with 40% methyl amine provided the title compound.

Calcd for C₂₂ H₂₈ N₂ O₂ : C, 74.97; H, 8.01; N, 7.95. Found: C, 74.67;H, 8.48; N, 7.88.

EXAMPLE 421 ##STR636##

To a stirred solution of 600 mg of the compound of example 249 in 10 mlof ethanol was condensed 1 ml of liquid ammonia and the mixture washeated in a pressure vessel to 85° C. under 200 psi for 4 hours. Themixture was cooled and filtered. The filtrate was concentrated undervacuo to give an oily gum which was chromatographed on silica using 85%CHCl₃ :14% ethanol:1% % NH₄ OH as mobile phase to provide 180 mg of thetitle compound.

Calcd for C₂₄ H₃₁ N₃ O₃ : C, 70.39; H, 7.63; N, 10.26 Found: C, 70.17;H, 7.92; N, 10.19

EXAMPLE 422 ##STR637##

150 mg (0.44 mmol) of the compound of example 265 were dissolved in 10ml of 40% methylamine (wt. % solution in water). A catalytic amount ofNaCN was added and the reaction was stirred at 50° C. for 2 hours. Thereaction was cooled and the mixture was diluted with 50 ml of H₂ O andthen extracted with two 25 ml portions of EA. The organic layers werecombined, 20 dried and concentrated. Chromatography was carried out on a1 mm chromatotron plate (90% EAℑ9% MeOHℑ1% triethylamine) to afford 100mg of pure product.

Calcd for C₂₀ H₂₆ N₂ O₂ 0.3 H₂ O: Calculated: C, 72.39; H, 8.08; N,8.44. Found: C, 72.36; H, 8.09; N, 8.22.

EXAMPLE 423 ##STR638##

The title compound was prepared essentially as described in Example 422except that ammonium hydroxide was used instead of methylamine.

Analysis Cald. for C₁₉ H₂₄ N₂ O₂ 0.3 H₂ O Calc: C, 71.81; H, 7.80; N,8.81. Found: C, 72.10; H, 7.94; N, 8.55.

EXAMPLE 424 ##STR639##

The title compound was prepared essentially as described in Example 422except that morpholine was used instead of methylamine.

Calc: C, 70.24; H, 8.00; N, 7.12. Found: C, 70.09; H, 8.13; N, 7.46.

EXAMPLE 425 ##STR640##

The product from Example 276 (0.20 g) was stirred in concentrated NH₄ OH(3 mL) with catalytic NaCN at reflux in a sealed vial for 23 h. Themixture was cooled and poured into EtOAc and water. The EtOAc layer wasseparated, washed with brine, dried over Na₂ SO₄ and concentrated. Flashchromatography on silica gel using a gradient of 99:1:0.5 to 97:3:0.5CH₂ Cl₂ /MeOH/NH₄ OH gave the title compound (0.052 g) as a colorlessoil: Anal. calc'd for C₂₀ H₂₄ N₂ O₂ : C, 74.05; H, 7.46; N, 8.63. Found:C, 74.12; H, 7.76; N, 8.44.

EXAMPLE 426 ##STR641##

The product from Example 275 (254 mg, 0.72 mmol) and a catalytic amountof sodium cyanide were dissolved in 10 mL ammonium hydroxide. Thereaction was refluxed for 12 hours. After cooling to RT, the reactionwas neutralized with 10% HCl. The aqueous phases was extracted with 4×30mL ethyl acetate. The combined organic extracts were dried (Na₂ SO₄),filtered, and concentrated to afford the crude product as a white solid.The product was chromatographed (silica gel, methanol/methylenechloride/ammonium hydroxide 2/97.5/0.5) to afford the pure product as awhite solid. The product had the following properties: mp 106°-107° C.Anal. calcd for C₂₂ H₂₇ NO₃ : C, 74.53; H, 7.74; N, 8.28. Found C,74.36; H, 7.66; N, 8.12.

EXAMPLE 427 ##STR642##

A solution of 153 mg of the product from example 305 in 5 mL of ethanoland 5 mL of concentrated ammonium hydroxide solution was prepared andplaced in a Parr bottle. The vessel was stoppered and stirred at roomtemperature for 48 hours. The reaction mixture was concentrated and theresidue was purified on prep plates eluting with 89.5% CHCl₃ -10.0%ethanol-0.5% NH₄ OH to yield 59 mg of white powder.

Analysis for C₂₁ H₂₆ N₂ O₃.1.0 H₂ O

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        67.72            C     67.82                                                  7.58             H     7.17                                                   7.52             N     7.35                                                   ______________________________________                                    

EXAMPLE 428 ##STR643##

To a stirred solution of the alcohol from example 385 (100 mg, 0.29mmol) in methylene chloride (5 ml) and triethylamine (0.5 ml, excess) at0° C., phenyl isocyanate was added. The reaction mixture was stirredovernight, evaporated and partitioned between ethyl acetate andsaturated potassium hydrogen sulfate solution. The organic layer wasseparated, washed with saturated potassium hydrogen carbonate solutionfollowed by brine. The organic extracts were dried (Na₂ SO₄) andevaporated to afford a white solid. The crude product was purified byradial chromatography (eluant:ethyl acetate)to afford the title compound(45 mg)

Anal. Calc. C₂₇ H₃₀ N₂ O₃ : Calc: C, 75.32; H, 7.02; N, 6.51. Found: C,74.96; H, 6.84; N, 6.70.

EXAMPLE 429 ##STR644##

To a stirred solution of the ester of example 245 in 8.0 ml of methanolwas added 2 ml of 1N NaOH solution. The mixture was heated and allowedto reflux for 1 hour. The reaction mixture was cooled to roomtemperature and the solvent removed by evaporation under reducedpressure to give a solid residue which was taken up in 10 ml of waterand neutralized with 2N HCl until it turned cloudy (pH=4.65). Thesolution was extracted with ethyl acetate and washed with water anddried over Na₂ SO₄. The solvent was removed by evaporation under reducedpressure to give an oily gum which was converted to HCl salt withethanolic HCl to give 33 mg of the title compound as a white solid.

Calcd for C₂₁ H₂₅ NO₃.HCl.H₂ O: Calculated: C, 64.03; H, 7.16; N, 3.56Found: C, 63.53; H, 6.70; N, 3.59

EXAMPLE 430 ##STR645##

The compound of example 228 (0.2 g) was hydrogenated over 4% Pd/C in 10ml 3A EtOH, 5 psi for 1.6 hrs. Concentration of the EtOH sol. gave 0.12g of the title product as white precipitate. The title compound wasrecrystallized from toluene (m.p. 165-169).

Analysis for C₂₁ H₂₄ NO₃.0.5H₂ O

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             72.60   72.88                                                   H             7.25    7.51                                                    N             4.03    3.96                                                    ______________________________________                                    

EXAMPLE 431 ##STR646##

800 mg of the compound of example 261 was hydrogenated over 4% Pd/C in3A EtOH 20 ml at 5 psi for 2 hr, filtered and recrystallized from 3AEtOH to provide 120 mg of the title compound (m.p. 165°-167°).

Analysis for C₁₉ H₂₃ NO₃.0.6H₂ O

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             70.39   70.15                                                   H             7.52    7.29                                                    N             4.32    4.24                                                    ______________________________________                                    

EXAMPLE 432 ##STR647##

0.1 g of the compound of example 417 was hydrogenated over 4% Pd/C inEtOH as described in example 431. Removal of the solvent in vacuofollowed by silica gel chromatography provided 80 mg of the titlecompounds as yellow oil.

Analysis for C₂₁ H₂₇ NO₃ 0.2C₇ H₈

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             74.76   74.28                                                   H             8.01    7.95                                                    N             3.89    3.34                                                    ______________________________________                                    

EXAMPLE 433 ##STR648##

The compound of example 273 was hydrogenated as was described forexample 431 to afford 70 mg of the title compound, m.p. 140-141.

Analysis for C₂₀ H₂₅ NO₃

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             73.37   73.36                                                   H             7.70    7.64                                                    N             4.28    4.20                                                    ______________________________________                                    

EXAMPLE 434 ##STR649##

The compound of example 411 was hydrogenated as example 431 to afford 30mg of the title compound as white needles (m.p. 113-116).

Analysis for C₂₀ H₂₅ NO₃.0.2EtoAc

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             72.40   72.10                                                   H             7.77    8.00                                                    N             4.06    4.41                                                    ______________________________________                                    

EXAMPLE 435 ##STR650##

The product from Example 325 (100 mg) was dissolved in 5 ml of freshlydistilled THF and was treated with 0.5 mL of 6N HCl and the mixture wasrefluxed for 4 hours. The reaction mixture was cooled to roomtemperature and was concentrated in vacuo to yield solid residue, whichupon crystallization from ether yielded 78 mg of title compound.

Calculated for C₂₁ H₂₃ NO₃.HCl: Calc: C, 65.88; H, 6.58; N, 3.66. Found:C, 66.06; H, 6.83; N, 3.36.

EXAMPLE 436 ##STR651##

To a stirred solution of example 309 (30 mg, 0.08 mmols) in THF (2.5 mL)was added 6N HCl (1 mL) at r.t. The resulting solution was heated to 85°C. for 5 hours. The reaction was concentrated in vacuo to give a stickygum. The residue was washed with Et₂ O and then slurried in EtOAc. Thesolid was collected by vacuum filtration to give 19 mg off-white solid.The resulting product had the following properties: Analysis calcd forC₂₁ H₂₅ NO₃ FCl 0.8 H₂ O: C, 61.78; H, 6.57; N, 3.43. Found: C, 61.41;H, 6.09; N, 3.26.

M⁺ =357.

                                      TABLE 16a                                   __________________________________________________________________________    Ex.                                                                           No. Compound                       Starting Material                                                                     Analysis                           __________________________________________________________________________    437                                                                               ##STR652##                     Ex. 310 C.sub.19 H.sub.24 NO.sub.3                                                    SCl0.8H.sub.2 O: Calc: C,                                                     57.58; H, 6.51; N, 3.53.                                                      Found: C, 57.61; H, 6.32; N,                                                  3.30. M.sup.+ = 345                438                                                                               ##STR653##                     Ex. 312 C.sub.21 H.sub.25 NO.sub.3                                                    FCl1H.sub.2 O: Calc: C, 61.24;                                                H, 6.61; N, 3.40. Found: C,                                                   61.27; H, 4.47; N, 3.40.                                                      M.sup.+ = 357                      439                                                                               ##STR654##                     Ex. 313 C.sub.19 H.sub.24 NO.sub.3                                                    SCl1.3H.sub.2 O: Calc: C,                                                     56.30; H, 6.61; N, 3.46.                                                      Found: C, 56.05; H, 6.22; N,                                                  3.37. M.sup.+ = 345                __________________________________________________________________________

EXAMPLE 440 ##STR655##

A solution of 20 mL of 3:1 concentrated hydrochloric acid-water and 725mg of the product from example 308 was refluxed for 12 hours. Thereaction mixture was concentrated and the residue repeatedly azeotropedwith toluene and then the residue was dried in vacuo. This material wasdissolved in 50 mL of anhydrous methanol and saturated with anhydrousHCl gas with chilling in an ice bath for 1 hour. The reaction mixturewas then degassed and concentrated to a small volume and partitionedbetween 10% K₂ CO₃ solution and ethyl acetate. The aqueous portion wasextracted with additional ethyl acetate and the combined organicextracts washed with saturated NaCl solution, dried over MgSO₄ andconcentrated. The product was purified on a silica gel column elutingwith 94.5% CH₂ Cl₂ -5.0% CH₃ OH-0.5% NH₄ OH to afford 333 mg of viscousoil.

Anal. for C₂₃ H₂₇ NO₃.0.25 H₂ O:

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        74.67            C     74.60                                                  7.49             H     7.66                                                   3.79             N     3.76                                                   ______________________________________                                    

EXAMPLE 441 ##STR656##

To a stirred solution of 300 mg of the amide of example 242 in 5 ml ofTHF containing 0.3 ml of pyridine was added 0.2 ml of trifluoroaceticanhydride at 0° C. and the mixture was stirred at 0° to 5° C. for 30minutes. The reaction was warmed up to room temperature and was allowedto stir at room temperature for 16 hours. The solvent was removed byevaporation under reduced pressure to give an oily gum which waschromatographed on silica gel using 92.5% CHCl₃ :7% ethanol and 0.5% NH₄OH as a mobile phase to give oily gum which was converted into HCl saltfollowed by crystallization from ether to provide the title compound.

Calcd for C₂₁ H₂₄ N₂ O.HCl.0.3 H₂ O: Calculated: C, 69.82; H, 7.12; N,7.73. Found: C, 69.36; H, 6.89; N, 7.66.

EXAMPLE 442 ##STR657##

To a stirred suspension of isonipecotamide (35 g, Aldrich) intriethyamine (36 mL) and CHCL3 (400 mL) at 0° C. was added ditertiarybutyldicarbonate (55 g, Aldrich). The mixture was allowed to warm toroom temperature over 3 hr. The volatiles were removed and the residuewas taken up in a mixture of CH₂ Cl₂ and ether. The organic solution waswashed with water, dried over MgSO₄ and concentrated in vacuo to givethe title compound, as a white solid (51 g).

EXAMPLE 443 ##STR658##

To a stirred solution of the product of Example 442 (51 g) in pyridine(175 mL) at 0° C. was added trifluoroacetic anhydride (38 mL) over 45min. The mixture was allowed to warm to room temperature over 16 hr. Themixture was concentrated in vacuo to 1/3rd its original volume andpoured into ice-cold water. The mixture was extracted with CHCl₃. Theorganic phase was washed with water (2 times), dried over MgSO₄ anddistilled in vacuo to give the title compound (32 g, Bp=110°-115°C./0.01 mm).

EXAMPLE 444 ##STR659##

Following the procedure described in example: 441 and replacing thecompound of example 242 with the compound of example 297 yields thetitle compound as HCl salt. Calcd. for C₂₂ H₂₆ N₂ O.HCl.0.25 H₂ O: Calc:C, 70.38; H, 7.38; N, 7.46 Found: C, 70.10; H, 7.00; N, 7.35

EXAMPLE 445 ##STR660##

To a stirred solution of 250 mg of the compound of example 444 in 10 mlof absolute ethanol containing 500 mg of triethylamine is added 250 mgof NH₂ OH.HCl and the mixture is heated to reflux and is allowed toreflux for 21/2 hours. The mixture is cooled to room temperature and isconcentrated in vacuo to provide a crude oily gum, which is extractedwith ethyl acetate. The organic extract is washed with water, dried overNa₂ SO₄ and concentrated in vacuo to give a residue which ischromatographed on silica gel using 85% CHCl₃, 14% ethanol, and 1% NHaOHas eluant to provide 166 mg of the title compound, as white solid.

Calcd. for C₂₂ H₂₉ N₃ O₂.1/4 H₂ O: Calc: C, 71.03; H, 7.99; N, 11.30Found: C, 71.28; H, 7.92; N, 11.16.

EXAMPLE 446 ##STR661##

To a stirred solution of the product of Example 284 (1.5 g) andhydroxylamine hydrochloride (0.38 g, Aldrich) in ethanol (10 mL) wasadded sodium ethoxide (0.38 g) and the mixture heated to reflux for 4 hand allowed to stand at room temperature for 2 days. The volatiles wereremoved and the residue chromatographed over silica gel using CHCl₃/Ethanol/Aqueous NH₃ 85/14/1, to give the title product as a colorlesssolid.

Anal. for C₂₂ H₂₇ N₃ O₂

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        72.30            C     72.03                                                  7.45             H     7.54                                                   11.50            N     11.21                                                  ______________________________________                                    

EXAMPLE 447 ##STR662##

The procedure of Example 446 was repeated using the product of Example441 in the place of the product of Example 284 to give the title productas a colorless solid.

Anal. for C₂₄ H₃₁ N₃ O₄.0.25 H₂ O

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        67.03            C     67.01                                                  7.38             H     6.98                                                   9.77             N     9.43                                                   ______________________________________                                    

EXAMPLE 448 ##STR663##

To a stirred solution of the product of Example 447 (0.45 g) in THF (10mL at -60° C. was added a toluene solution of phosgene (0.931M, 3.3 mL,Fluka). The mixture was allowed to warm to room temperature over 16 hr.The volatiles were removed and the residue chromatographed over silicagel using CHCl3/Ethanol/Aqueous NH3 25/10/1, to give the title productas a colorless hygroscopic solid.

Anal. for C₂₂ H₂₅ N₃ O₃.0.5 H₂ O

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        68.02            C     68.00                                                  6.75             H     6.54                                                   10.82            N     10.89                                                  ______________________________________                                    

EXAMPLE 449 ##STR664##

A solution of the product of Example 447 (0.576 g) in ethanol (15 mL)and acetic acid (3 mL) was hydrogenated in a parr hydrogenationapparatus over 4% Pd/C under 60 psi of hydrogen pressure for 24 hr. Thesolution was filtered and the filtrate concentrated. The residue waschromatographed over reverse phase silica gel using methanol/water aseluant of provide the free base of the title product. This material wastaken in a small volume of ethanol and saturated ethanol HCl was added.The mixture was concentrated. The residue was dried at 78° C./0.5 mm togive the title compound as a sticky solid.

Anal. for C₂₁ H₂₇ N₃ O.1.9 HCl.0.75 H₂ O

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        60.02            C     59.99                                                  7.29             H     7.18                                                   10.00            N     9.50                                                   16.03            Cl    16.12                                                  ______________________________________                                    

EXAMPLE 450 ##STR665##

The product from Example 441 (350 mg) was dissolved in xylene (15 ml)and was treated with NaN₃ (220 mg), tributyltin chloride (0.38 ml) andLiCl (140 mg), and the mixture was heated to reflux under nitrogen atm.and was allowed to reflux for 20 hours. The mixture was cooled to roomtemperature and concentrated in vacuo to afford an oily gum which wastaken up in methanol (˜20 ml) and filtered. The filtrate wasconcentrated in vacuo to provide an oily gum which upon reverse phasecolumn chromatography yielded 182 mg of the title compound as whitesolid.

Calculated for c₂₁ H₂₅ N₅ O.0.6 H₂ O: Calc: C, 67.39; H, 7.06; N, 18.71.Found: C, 66.97; H, 6.87; N, 19.10.

EXAMPLE 451 ##STR666##

Following the procedure described in Example 450, and replacing theproduct of Example 441, with the product of Example 444, provided thetitle compound as white solid.

Calculated for C₂₂ H₂₇ N₅ O.H₂ O: Calc: C, 66.81; H, 7.39; N, 17.71.Found: C, 67.12; H, 7.10; N, 17.63.

EXAMPLE 452 ##STR667##

The product from Example 256 (1.12 g, 3.3 mmol) was dissolved in 50 mL1.2N HCl and stirred at 100° C. for 12 hours. The reaction was cooled toRT and made basic with 10% NaOH. The aqueous phases was extracted with5×40 mL ethyl acetate. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated to afford a brown oil. The product hadthe following properties: Anal. calcd for C₁₉ H₂₄ N₂ O.0.70 H₂ O:Calculated: C, 73.85; H, 8.28; N, 9.07. Found: C, 73.79; H, 8.09; N,8.84.

EXAMPLE 453 ##STR668## SC-57244

The product from Example 452 (645 mg, 2.16 mmol) andtrimethylsilylisocyanate (364 mg, 3.16 mmol) were dissolved in 10 mLTHF. The reaction was stirred for 12 hours at RT under argon. Thereaction was quenched with 10 mL methanol. The solvent was concentratedin vacuo and the residue was dissolved in 20 mL methylene chloride. Theorganic phases was washed with 3×20 mL water and dried (Na₂ SO₄) toafford the crude product as a tan solid. The solid was recrystallizedfrom methanol/diethyl ether to give the pure product as a tan solid. Theproduct had the following properties: mp 132°-134° C. Anal. calcd forC₂₀ H₂₅ N₃ O₂.0.10 H₂ O: C, 70.40; H, 7.44; N, 12.31. Found C, 70.36; H,7.47; N, 12.22.

EXAMPLE 454 ##STR669##

To a stirred solution of the amine from example 452 (100 mg, 0.34 mmol)in methylene chloride (1 ml) at room temperature, chloroacetyl chloride(30 μmol, 1.1 eq) was added. The reaction mixture was stirred at roomtemperature for 10 min, evaporated and the residue crystallized fromdiethyl ether to afford the title compound (111 mg)

Anal. calc. C₂₁ H₂₅ N₂ O₂ Cl.0.1HCl 0.25 H₂ O: Calc: C, 60.80; H, 6.68;N, 6.75. Found: C, 60.72; H, 6.38; N, 6.53.

EXAMPLE 455 ##STR670##

The title compound was prepared from the compound of example 238 (500mg) in a manner identical to that described in example 452. Thisafforded the title compound as a white solid (401 mg)

Anal. calc. C₂₀ H₂₆ N₂ O₂ HCl 0.5 H₂ O: Calc: C, 61.22; H, 7.45; N,7.14. Found: C, 61.20; H, 7.50; N, 7.07.

EXAMPLE 456 ##STR671##

To a stirred solution of the amine from example 455 (180 mg, 0.47 mmol)and triethylamine (1 ml) in THF(4 ml) trimethylsilyl isocyanate (70 μl,1.5 eq) was added. The reaction mixture was stirred at room temperaturefor 3 h, evaporated and the crude product precipitated from diethylether to afford the title compound (175 mg)

Anal. calc. C₂₁ H₂₇ N₃ O₂.0.4 H₂ O: Calc: C, 69.93; H, 7.77; N, 11.65.Found: C, 69.80; H, 7.69; N, 11.78.

EXAMPLE 457 ##STR672##

A mixture of the product of Example 277 and excess of 3N HCl was heatedon a steam-bath for 16 hr. The volatiles were removed in vacuo toprovide the title compound as a white solid.

Anal. calc. for C₁₉ H₂₄ N₂ O.2HCl

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        61.79            C     61.31                                                  7.10             H     7.32                                                   7.58             N     7.49                                                   19.20            Cl    18.94                                                  ______________________________________                                    

EXAMPLE 458 ##STR673##

A mixture of the free base of the product of Example 457 (0.23 g),trimethylsilylisothiocyanate (0.81 mL, Aldrich), K2CO3 (100 mg) andtoluene (5 mL) was heated to reflux for 16 hours. The mixture wasconcentrated and the residue chromatographed on silica gel usingCHCl3/ethanol/aqueous NH₃, 85/14/1, to give the title product as asolid.

Anal. for C₂₀ H₂₅ N₃ OS.0.25 H₂ O

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        66.73            C     66.87                                                  7.14             H     6.91                                                   11.67            N     11.65                                                  8.91             S     8.88                                                   ______________________________________                                    

EXAMPLE 459 ##STR674##

The procedure of Example 458 was repeated using trimethylsilylisocyanate in the place of trimethylsilyl isothiocynate to provide thetitle product as a solid.

Anal. for C₂₀ H₂₅ N₃ O₂

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        70.77            C     70.54                                                  7.42             H     7.75                                                   12.38            N     12.31                                                  ______________________________________                                    

EXAMPLE 460 ##STR675##

To a stirred solution of the free base of the product of Example 457(0.33 g), and diisopropylethylamine (0.22 mL) in CH₂ Cl₂ (5 mL) at -78°C. was added methane sulfonylchloride (0.09 mL). The mixture was allowedto warm to room temperature over 1 hr. To the reaction mixture was addedsaturated aqueous NaHCO₃ and extracted with ethyl acetate. The organicextract was washed with water, dried over MgSO₄ and concentrated invacuo. The residue was crystallized from CH₂ Cl₂ to give the titleproduct as a white solid as carbondioxide adduct.

Anal. calc. for C₂₀ H₂₅ N₃ OS. CO₂

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        60.27            C     60.18                                                  6.26             H     6.62                                                   6.69             N     6.65                                                   7.66             S     7.80                                                   ______________________________________                                    

EXAMPLE 461 ##STR676##

To a stirred solution of N-t-butyloxycarbonyl-4-hydroxypiperidine (3.00g) and imidazole (2.7 g) in DMF (5 ml) at room temperature,t-butyldiphenylsilyl chloride (4.5 g) was added. The reaction mixturewas stirred at room temperature overnight, quenched into water and theaqueous solution extracted into diethyl ether. The organic extracts werecombined, dried (Na₂ SO₄) and evaporated to afford a clear oil. Thecrude product was purified by chromatography on silica (eluant,hexane/diethyl ether, 90/10) to afford the title compound (6.30 g)

Anal. calc. C₂₆ H₃₇ NO₃ Si: Calc: C, 71.03; H, 8.48; N, 3.19. Found C,71.26; H, 8.39; N, 2.76.

EXAMPLE 462 ##STR677##

To a stirred solution of the product from example 461 (800 mg) indiethyl ether (5 ml) and TMEDA (1 ml) at -78°, sec butyl lithium wasadded. The reaction mixture was stirred at -78° for 3 hr and thenquenched with methyl iodide (1 ml) The reaction mixture was allowed toattain room temperature and then partitioned between diethyl ether andwater. The organic layer was separated, dried (Na₂ SO₄) and evaporated.The crude product was purified by chromatography on silica (eluant,hexane/diethyl ether, 75/25) to yield the title compound (650 mg).

EXAMPLE 463 ##STR678##

To a stirred solution of the product from example 462 (110 mg) inmethylene chloride (1 ml) at room temperature, trifluoroacetic acid (2ml) was added. The reaction mixture was stirred at room temperature for10 mins, evaporated and the residue partitioned between diethyl etherand saturated potassium hydrogen carbonate solution. The organic layerwas separated, dried (Na₂ SO₄) and evaporated to afford a clear oil. Thecrude product was converted into its hydrochloride and crystallized fromethanol/diethyl ether to afford the title compound (40 mg)

Anal. calc. C₂₂ H₃₁ NOSi 1HCl.1H₂ O: Calc: C, 64.76; H, 8.40; N, 3.43.Found: C, 64.60; H, 7.97; N, 3.47.

EXAMPLE 464 ##STR679##

The title compound was prepared from the acid described in example 380(1.89 mg) and the product from example 463 (2.3 g) in a manner analogousto that described in example 389. This afforded the title compound (2.55g).

EXAMPLE 465 ##STR680##

The title compound was prepared from the product of example 464 (2.5 g)in a manner identical to that described in example 397. This affordedthe title compound (920 mg, 66%)

Anal. calc. C₂₁ H₂₇ NO₂.1HCl.0.4 H₂ O: Calc: C, 68.33; H, 7.86; N, 3.79.Found: C, 68.45; H, 8.12; N, 3.74.

EXAMPLE 466 ##STR681##

To a stirred solution of the product from example 464 (2.0 g) in THF (10ml) at room temperature, TBAF (5 ml) was added. The reaction mixture wasstirred at room temperature overnight, evaporated and the crude residuepartitioned between ethyl acetate and saturated potassium hydrogencarbonate solution. The organic extracts were separated, dried (Na₂ SO₄)and evaporated to afford the crude intermediate alcohol as a clear oil(1.80 g).

To a stirred solution of the above alcohol (1.8 g) in pyridine (10 ml)at 0°, toluene-4-sulfonyl chloride (800 mg) was added. The reactionmixture was stirred at room temperature for 24 h, evaporated and theresidue partitioned between ethyl acetate and saturated potassiumhydrogen carbonate solution. The organic extracts were separated, dried(Na₂ SO₄) and evaporated to afford a yellow oil. The crude product waspurified by chromatography on silica (eluant, diethyl ether) to affordthe title compound (500 mg).

EXAMPLE 467 ##STR682##

To a stirred solution of the product from example 466 (400 mg 0.81 mmol)in DMF (5 ml) at 60°, sodium azide was added. The reaction mixture wasstirred at 60° for 10 hr, evaporated and the residue partitioned betweendiethyl ether and water. The organic extracts were dried (Na₂ SO₄), andevaporated to afford the crude intermediate azide (210 mg). To a stirredsolution of the above azide (210 mg,) in methanol (5 ml) over a hydrogenatmosphere, 5% Pd/C was added. The reaction mixture stirred at roomtemperature for 1 hr, evaporated and the residue suspended/dissolved inethyl acetate. The organic solution was filtered (to remove thecatalyst) and evaporated to afford the intermediate amine (150 mg). To astirred suspension of lithium aluminum hydride (50 mg) in THF (4 ml) atroom temperature the above amine was added. The reaction mixture wasstirred at room temperature for 30 mins, quenched with water (200 mg)and then diluted with ethyl acetate (20 ml). The reaction mixture wasfiltered and the filtrate evaporated to afford the intermediate diamine(80 mg). To a stirred solution of the above diamine (70 mg) in aceticanhydride (1 ml) at room temperature, pyridine (3 drops) was added. Thereaction mixture was stirred at room temperature for 15 mins, quenchedwith saturated sodium hydrogen carbonate solution and extracted intoethyl acetate. The organic extracts were dried (Na₂ SO₄), evaporated,and the crude product was precipitated from diethyl ether to afford thetitle compound (62 mg).

Anal. calc. C₂₃ H₃₀ N₂ O₂. Calculated: C, 75.38; H, 8.25; N, 7.64.Found: C, 76.05; H, 8.89; N, 6.70.

EXAMPLE 468 ##STR683##

To a stirred solution of 100 ml of CH₂ Cl₂ and 100 ml of 15M NH₄ OHsolution is added 10.0 g of 2-chloro-6-methyl-4-pyridinecarbonylchloride, and the mixture is stirred at room temperature for 30 minutes,during which time white solid is precipitated out of the mixture whichis filtered and dried to provide 7.8 g of white solid. A solution of 5.5g of the white solid in 55 ml of ethanol is exposed to hydrogen gas inparr bomb at 140° C. at 1000 psi pressure for 18 hours. The mixture iscooled to room temperature. The catalyst is removed by filtration andthe filtrate is concentrated in vacuo to provide 5.4 g of title compoundas white crystaline solid.

EXAMPLE 469 ##STR684##

Following the procedure described in example: 468 and replacing NH₄ OHwith ethanol provides the title compound.

EXAMPLE 470 ##STR685##

Following the procedure described in example: 468 and replacing NH₄ OHwith 40% CH₃ NH₂ provides the title compound.

EXAMPLE 471 ##STR686##

To a stirred suspension of nor-tropinone hydrochloride (REF) (9.2 g) inDMF (100 mL) at 0° C. was added K₂ CO₃ (10 g). After 5 min., benzylbromide (7 mL) was added and the mixture allowed to warm to roomtemperature over 16 hr. The mixture was extracted with ethyl acetate andwater. The organic phase was washed four times with water, dried overMgSO₄ and concentrated. The residue was chromatographed over silica gelusing CHCl₃ containing 0.5% ethanol and a trace of aqueous NH₃ to givethe title product as a colorless thick liquid (12.8 g).

EXAMPLE 472 ##STR687##

To a stirred solution of trimethylsilyldithiane (9.2 mL, Aldrich) in THF(175 mL) at 0° C. was added in drops, n-butyl lithium (30.3 mL, 1.6Mcyclohexane solution). After 45 min., the product of Example 471 (12.8g) in THF (20 mL) was added in drops. After 20 min., water and etherwere added to the reaction mixture. The organic phase was dried overMgSO₄ and concentrated to give the title compound as a thick foulsmelling liquid (15.52 g).

EXAMPLE 473 ##STR688##

To a stirred solution of the product of Example 472 (15.52 g) inmethanol (480 mL) was added aqueous HCl (6N, 20.4 mL), HgCl2 (28 g) andtrifluoro acetic acid (9.5 mL). The mixture was heated to reflux for 3hr. The mixture was filtered through celite. The filtrate wasconcentrated and the residue chromatographed using CHCl₃/Ethanol/aqueous NH₃, 100/5/0.1, as eluant to provide the title compoundas a thick liquid.

EXAMPLE 474 ##STR689##

A solution of the product of Example 473 in methanol and Conc. HCl (2mL) was shaken in a parr hydrogenated apparatus over 40% Pd(OH)2/C under60 psi hydrogen pressure at room temperature. After the uptake ofhydrogen ceased, the solution was filtered and the filtrate concentratedin vacuo to give the title product.

EXAMPLE 475 ##STR690##

Methyl-1-benzyl-5-oxo-3-pyrrolidine carboxylate (25 g, 0.11 mol) wasdissolved in 200 mL THF under argon. Lithium aluminum hydride (6.5 g,0.17 mol) was added slowly to the THF. After the addition was complete,the reaction was refluxed for 31/2 hours. The reaction was cooled to RTand quenched with water/diethyl ether. After filtering and concentratingin vacuo, the crude product was obtained as a yellow oil. The oil waschromatographed (silica gel, methanol/methylene chloride/ammoniumhydroxide 5/94/1) to afford the pure product as a yellow oil. Theproduct had the following properties: Anal. calcd for C₁₂ H₁₇ NO.0.10 H₂O: C, 74.75; H, 8.98; N, 7.25. Found C, 74.66; H, 9.35; N, 7.20.

EXAMPLE 476 ##STR691##

The product from Example 475 (0.46 g, 2.4 mmol) and thionyl chloride(1.5 mL, 20.6 mmol) were refluxed in 5 mL chloroform for 2 hours. Thereaction was concentrated in vacuo, and the residue was dissolved in 20mL water. 10% NaOH was added until the pH was ˜8. The aqueous phase wasextracted with 5×30 mL ethyl acetate. The combined organic phases weredried (Na₂ SO₄), filtered and concentrated in vacuo to afford thechloride as an amber oil. The product had the following properties:Anal. calcd for C₁₂ H₁₆ NCl.0.20 H₂ O: C, 67.57; H, 7.75; N, 6.57; Cl,16.62. Found C, 67.57; H, 7.44; N, 6.48; Cl, 16.47.

EXAMPLE 477 ##STR692##

The product from Example 476 (2.52 g, 12 mmol), sodium cyanide (3 g, 61mmol) and aliquot 336 (156 mg, 0.38 mmol) were stirred in 5 mL water at100° C. for 48 hours. The reaction was cooled to RT and poured into 50mL water. The aqueous phase was extracted with 4×40 mL ethyl acetate.The combined organic extracts were dried (Na₂ SO₄), filtered andconcentrated to afford the crude product as a dark yellow oil. The oilwas chromatographed (silica gel, methanol/methylene chloride/ammoniumhydroxide 1/98.5/0.5) to give the pure product as a yellow oil. Theproduct had the following properties: Anal. calcd for C₁₃ H₁₆ N₂.0.08 H₂O: C, 77.40; H, 8.07; N, 13.89. Found C, 77.46; H, 8.37; N, 13.84.

EXAMPLE 478 ##STR693##

The product from Example 477 (1.08 g, 5.4 mmol) was dissolved in 50 mLmethanol and cooled to 0° C. Acetyl chloride (25 mL, 35 mmol) was addedslowly to the methanol. The reaction was stirred at RT for 12 hours. Thesolvent was concentrated in vacuo, and the residue was dissolved in 10mL water. To the water was added 25 mL saturated sodium bicarbonate. Theaqueous phase was extracted with 4×50 mL ethyl acetate. The combinedorganic extracts were dried (Na₂ SO₄), filtered and concentrated toafford the crude ester as a yellow oil. The HCl salt was prepared bydissolving the ester in 5 mL diethyl ether and adding 3M ethanolic HCldropwise. The pure HCl salt was obtained as a yellow oil. The producthad the following properties: Anal. calcd for C₁₄ H₂₀ NO₂ Cl.0.65 H₂ O:C, 59.74; H, 7.63; N, 4.98. Found C, 59.68; H, 7.75; N, 5.05.

EXAMPLE 479 ##STR694##

The product from Example 478 (1.04 g, 3.8 mmol) and 1,4-cyclohexadiene(5 mL, 52 mmol) were dissolved in 20 mL methanol. The reaction flask wasflushed with argon and 10% Pd/C (1.02 g) was added portionwise. Thereaction was refluxed for 12 hours under argon. The reaction wasfiltered through Celite/silica gel. The solvent was concentrated invacuo to afford the product as a yellow waxy solid. The product had thefollowing properties: H.R.M.S. M+1 calcd for C₇ H₁₃ NO₂ : 144.1025.Found 144.1011.

EXAMPLE 480 ##STR695##

To a solution of N-benzyl-N-(trimethylsilylmethyl)-aminoacetonitrile(7.6 g, 32.7 mmol) and methyl acrylate (3.0 mL, 33.3 mmol) in CH₃ CN (60mL) was added AgF (4.5 g, 35.5 mmol) and the mixture stirred in the darkat 25° C. for 19 h. The mixture was filtered and concentrated. Flashchromatography using a gradient of 10:1 to 3:1 hexane/EtOAc provided thetitle compound (3.3 g, 46%) as a colorless oil.

EXAMPLE 481 ##STR696##

The product from Example 480 (3.3 g, 15 mmol) was submitted to 60 psi H₂in a Parr shaker in EtOH with catalytic Pd(OH)₂ at 25° C. for 3 h. Thesolution was filtered and concentrated to provide the title compound.

EXAMPLE 482 ##STR697##

To a stirred solution of 2.28 g of BOC-isonipecotic acid in 10 ml ofN,N-dimethylformamide was placed 2.56 g of N,N-disuccinimidyl carbonateand 2 ml of pyridine. The mixture was treated with 20 mg ofN,N-4-dimethylamino pyridine and 1.0 g of triethylamine. The reactionmixture was stirred at room temperature under nitrogen atmosphere for 40minutes. 1.53 g of β-alanine ethyl ester hydrochloride was added to themixture. The mixture was stirred at room temperature for 16 hrs. Themixture was poured into water and extracted with ethyl acetate. Theorganic extract was washed with a saturated solution of KHCO₃, and waterand saturated solution of KHSO₄ (KHCO₃ or KHSO₄) and dried over Na₂ SO₄.The solvent was removed by evaporation under reduced pressure to givecrude oily gum which was taken up in 10 ml of 90% trifluoroacetic acidand was allowed to stir at room temperature for 30 minutes. The solventwas removed by evaporation under reduced pressure to give 1.6 g of titlecompound which was used in Example 249 without further purification.

EXAMPLE 483 ##STR698##

Following the procedure described in example 482 and replacing β-alanineethyl ester hydrochloride with 40% methylamine provided the titlecompound as TFA salt which was taken up to the next step without furtherpurification.

EXAMPLE 484 ##STR699##

3-Pyrroline (6.91 g, 100 mmoles) was dissolved in 150 ml of 80:20mixture of dioxane:H₂ O and was treated with 25 ml of Et₃ N and themixture was stirred at room temperature for 10 minutes. Di-tert-butyldicarbonate (18.6 g, 100 mmoles) was added and the mixture was stirredat 25° C. for 6 hours. The mixture was concentrated in vacuo to yieldoily residue, which was dissolved in ethyl acetate (˜100 ml), and waswashed with water, dried over Na₂ SO₄, filtered and the filtrate wasconcentrated in vacuo to provide 8.6 g. The title compound whose H¹ NMR300 MHz spectrum was consistent with proposed structure.

EXAMPLE 485 ##STR700##

The compound was prepared following the methodology described inEuropean patent EP 0 413 455 A2 and replacing1-benzyloxycarbonyl-3-pyrroline with the product from Example 484. H¹NMR 300 MHz spectrum was consistent with proposed structure.

EXAMPLE 486 ##STR701##

The product from Example 485 (1 g) was taken up in ml of CH₂ Cl₂ and wastreated with 2 ml of TFA and the mixture was stirred at room temperaturefor 3 hours. The mixture was concentrated in vacuo to provide 1.15 g oftitle compound as oil whose H¹ NMR 300 MHz spectrum was consistent withproposed structure.

EXAMPLE 487 ##STR702##

A solution of 2.4 g of 2-(carbobenzyloxy)2-azabicyclo 2.2.1!heptan-5-one(J. Med. Chem. 1992, 35, 2184-2191), 6.7 g ofmethyl(triphenylphosphoranylidene)acetate (Aldrich), 25 mL toluene and10 mL THF was refluxed for 14 hours under N₂. The reaction mixture wascooled, concentrated and purified on a silica gel column eluting with30% ethyl acetate in hexane to yield 2.31 g of a tinted liquid. The NMRspectra was consistent for the proposed structure.

EXAMPLE 488 ##STR703##

A mixture of 2.3 g of the product from example 487, 1.8 g of magnesiumturnings, and 80 mL of anhydrous methanol was stirred under N₂ withcooling in a water bath until all of the metal had dissolved (˜4 h). A100 mL portion of 3N HCl was added and stirred for 5 minutes and thenconcentrated to a volume of approximately 50 mL. The aqueous residue wasextracted thoroughly with ether, the organic extracts concentrated andthe residue purified on a silica gel column eluting with 40% ethylacetate in hexane to yield 1.4 g of colorless liquid. The NMR spectrawas consistent for the proposed structure.

EXAMPLE 489 ##STR704##

A solution of 1.3 g of the product from example 488 and 4.5 mL of 1N HClin 50 mL of methanol was decarbobenzyloxylated under an atmosphere ofhydrogen using 50 mg of 5% palladium on carbon catalyst at roomtemperature for 16 hours. The reaction mixture was filtered through apad of celite and the filtrate concentrated. The residue, 700 mg, wasused directly in the next step without further purification. The NMRspectra was consistent for the proposed structure.

EXAMPLE 490 ##STR705##

A solution of 4.9 g of 2-(carbobenzyloxy)-2-azabicyclo2.2.1!heptan-6-one (J. Med. Chem. 1992, 35, 2184-2191) in 75 mL oftoluene was reacted with 10.0 g ofmethyl(triphenylphosphoranylidene)acetate (Aldrich) as described inExample 487. The reaction was worked up and purified in the same mannerto produce 6.9 g of colorless oil. The NMR spectra was consistent forthe proposed structure.

EXAMPLE 491 ##STR706##

A mixture of 6.7 g of the product from example 490, 5.4 g of magnesiumturning and 500 mL of anhydrous methanol was reacted as described inExample 488. The product was isolated as previously described to afford5.0 g of viscous oil. The NMR spectra was consistent for the proposedstructure.

EXAMPLE 492 ##STR707##

A 1.4 g quantity of product from example 491 was decarbobenzyloxylatedas described in Example 489. The product was isolated as previouslydescribed to yield 1.0 g of white solid. The NMR spectra was consistentfor the proposed structure.

EXAMPLE 493 ##STR708##

A mixture of 3.0 g of N-benzyl-4-piperidone (Aldrich), 2.0 g oftrimethylsilylcyanide (Aldrich), 64 mg of zinc iodide and 20 mL of CH₂Cl₂ was refluxed for 18 hours under N₂. The reaction mixture was cooledand blown down under N₂ and then concentrated in vacuo. The residue wasdissolved in 7 mL of concentrated hydrochloric acid and stirred at roomtemperature for 30 hours. The reaction mixture was then concentrated todryness and the residue repeatedly azeotroped with toluene and thendried in vacuo. The residue was dissolved in 75 mL of methanol andanhydrous HCl gas was bubbled into the solution for 1 hour with chillingin an ice bath. The excess HCl was removed by bubbling N₂ through thesolution and then the reaction mixture was concentrated and partitionedbetween 10% K₂ CO₃ solution and ethyl acetate. The aqueous portion wasextracted several times with ethyl acetate and the combined organicextracts were concentrated and purified on a silica gel column elutingwith 97.5% CHCl₃ -2.0% CH₃ OH-0.5% NH₄ OH to afford 1.5 g of whitesolid. The NMR spectra was consistent for the proposed structure.

EXAMPLE 494 ##STR709##

A mixture of 1.5 g of the product from example 493 in methanolcontaining excess dilute HCl solution was debenzylated using 20%palladium hydroxide on carbon at 5 psi for 20.6 hours at roomtemperature. The reaction mixture was filtered through a pad of celiteand the filtrate was concentrated. The residue was azeotroped severaltimes with toluene and then dried in vacuo. The NMR spectra wasconsistent for the proposed structure.

EXAMPLE 495 ##STR710##

A mixture of 12.0 g (31.4 mmol) of tosylate described in example 186,3.2 g (50.1 mmol) of sodium azide and 100 mL of DMF were heated at 60°C. for 5 hours under N₂. The reaction mixture was cooled and partitionedbetween water and ether. The aqueous portion was extracted several timeswith ethyl acetate and the combined organic extracts were washed withsaturated sodium chloride solution and dried over sodium sulfate,filtered and the filtrate concentrated to afford 8.5 g of golden liquidwhich was used without further purification.

NMR (CDCl₃) S 3.47 (t, 2H), 3.89 (S, 2H), 4.03 (t, 2H), 6.8-7.3 (complexband, 9H).

EXAMPLE 496 ##STR711##

In a flame dried flask under N₂ was made a suspension of 2.30 g (60.6mmol) of lithium aluminum hydride in 100 mL of anhydrous ether. Themixture was stirred and chilled to -70° C. while a solution of 8.5 g(33.6 mmol) of the azide from example 495 in 50 mL of anhydrous etherwas added dropwise. The reaction mixture was allowed to warm to roomtemperature and stirred for 3 hours. The reaction was then quenched bycareful addition of 2.3 mL water, 2.3 mL of 15% aqueous sodium hydroxidesolution, and 6.9 mL of water. The white suspension was stirred for 30minutes, filtered, and the filtrate concentrated to produce 6.40 g ofviscous oil which solidified upon chilling.

NMR (CDCl₃) S 3.92 (t, 2H), 3.90 (S, 2H), 3.04 (t, 2H), 1.48 (broadband, 2H), 6.8-7.3 (complex band, 9H).

EXAMPLE 497 ##STR712##

In a Parr bottle was placed 568 mg of 1,3 cyclopentadiene, 704 mg of 37%aqueous formaldehyde solution, 1.5 g of amine from example 496 and 6.6mL of 1N HCl. The bottle was stoppered and the contents vigorouslystirred at room temperature for 18 hours. The reaction mixture waspartitioned between 2N NaOH solution and ethyl acetate. The aqueousportion was extracted several times with ethyl acetate and the combinedorganic extracts were washed with water, saturated NaCl solution, driedover Na₂ SO₄ and concentrated. The residue was purified on a silica gelcolumn eluting with 97.0% CH₂ Cl₂ -2.5% CH₃ OH-0.5% NH₄ OH to afford 817mg of product. m.p. 37°-38°.

Anal. for C₂₁ H₂₃ NO.0.05 H₂ O

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        82.34            C     82.02                                                  7.60             H     8.01                                                   4.57             N     4.54                                                   ______________________________________                                    

EXAMPLE 498 ##STR713##

In a Parr bottle was placed 801 mg of 1,3 cyclohexadiene, 819 mg of 37%aqueous formaldehyde solution, 2.0 g of amine from example 496 and 8.8mL of 1N HCl. The bottle was stoppered and the contents vigorouslystirred at 55° for 48 hours. The reaction was worked up and purified asdescribed in Example 497 to yield 375 mg of a light brown viscous oil.

Anal. for C₂₂ H₂₅ NO.0.2 H₂ O

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        81.80            C     81.57                                                  7.93             H     8.10                                                   4.34             N     4.51                                                   ______________________________________                                    

EXAMPLE 499 ##STR714##

A solution of 171 mg of product from example 497 in ethanol washydrogenated in a Parr shaker at room temperature and 5 psi for 1 hourusing 4% palladium on carbon catalyst. The reaction mixture was filteredthrough a pad of celite, concentrated, and purified on a silica gelcolumn eluting with 97.0% CH₂ Cl₂ -2.5% CH₃ OH-0.5% NH₄ OH to yield 130mg of viscous oil.

Anal. for C₂₁ H₂₅ NO.0.2 H₂ O

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        81.09            C     80.89                                                  8.23             H     8.42                                                   4.50             N     4.53                                                   ______________________________________                                    

EXAMPLE 500 ##STR715##

A solution of 133 mg of product from example 498 in ethanol washydrogenated and purified as described in example 499 to afford 88 mg ofoil.

Anal. for C₂₂ H₂₇ NO.0.25 H₂ O

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        81.06            C     80.77                                                  8.50             H     8.46                                                   4.30             N     4.21                                                   ______________________________________                                    

EXAMPLE 501 ##STR716##

A mixture of 10 g of 5-norbornene-2-carboxylic acid (Pfaltz & Bauer),11.1 g of K₂ CO₃, 12.1 g of methyl iodide (Aldrich) and 75 mL of DMF wasstirred at room temperature for 18 hours. The reaction mixture waspartitioned between ether and water and then the aqueous portion wasextracted with ethyl acetate several times. The combined organicextracts were washed twice with saturated NaCl solution, dried over Na₂SO₄, concentrated and the residue purified on a silica gel columneluting with 2.5% ethyl acetate in hexane to yield 6.2 g of a colorlesssweet smelling liquid. The NMR spectra was consistent for the proposedstructure.

EXAMPLE 502 ##STR717##

A mixture of 4.0 g of the product from example 501, 2.5 g of 4-methylmorpholine-N-oxide (Aldrich), 2 mL of a 2% solution of osmium tetroxidein isopropanol (Aldrich), 50 mL of water, and 50 mL of acetone wasstirred under N₂ at room temperature for 18 hours. The reaction mixturewas then partitioned between ethyl acetate and saturated NaCl solutionand the aqueous portion was then extracted four times with additionalethyl acetate. The combined organic extracts were concentrated and theresidue was purified on a silica gel column eluting with ethyl acetateto afford 4.6 g of a tan solid. The NMR spectra was consistent for theproposed structure.

EXAMPLE 503 ##STR718##

To a solution of 4.5 g of the product from example 502 in 100 mL oftert-butanol was added dropwise at room temperature a solution of 6.9 gof sodium periodate (Aldrich) in 25 mL of water. The resulting whitesuspension was stirred for 30 minutes and then filtered through a pad ofcelite. The filtrate was concentrated and the residue was purified on asilica gel column eluting with 80% ethyl acetate and 20% hexane toproduce 1.6 g of a colorless liquid. The NMR spectra was consistent forthe proposed structure.

EXAMPLE 504 ##STR719##

To a solution of 300 mg of amine hydrochloride from example 496 in 5 mLof methanol at 0° under N₂ was added 221 mg of the product from example503 in 1 mL of methanol. The reaction was stirred for 5 minutes and then126 mg of sodium cyanoborohydride (Aldrich) was added as a solid inportions over 10 minutes. The reaction was allowed to warm to roomtemperature, stirred overnight and then partitioned between 10% K₂ CO₃solution and ethyl acetate. The aqueous portion was extracted severaladditional times with ethyl acetate and the combined organic extractswere concentrated and purified on silica gel column eluting with 40%ethyl acetate in hexane to afford 190 mg of a colorless oil.

Anal. for C₂₄ H₂₉ NO₃

    ______________________________________                                        Calculated             Found                                                  ______________________________________                                        75.96            C     75.62                                                  7.70             H     7.60                                                   3.69             N     3.59                                                   ______________________________________                                    

EXAMPLE 505 ##STR720##

A solution of 3.0 g of 2-(carbobenzyloxy)-2-azabicyclo2.2.1!heptan-5-one (J. Med. Chem. 1992, 35, 2184-2191) and 1.2 g oflithium cyanide (Johnson & Matthey) in 40 mL of dry THF was stirred atroom temperature under N₂. A solution of 6.0 g ofdiethylcyanophosphonate (Aldrich) in 10 mL of dry THF was then added inone portion and the reaction stirred for 30 minutes. The reaction wasquenched with 100 mL of water and extracted with ethyl acetate severaltimes. The combined organic extracts were washed with saturated NaClsolution, dried over Na₂ SO₄ and concentrated. The residue wasazeotroped several times with toluene. This material was dissolved in 25mL of dry THF and 1.2 mL of tert-butanol and added to 367 mL of a 0.1Msolution of samarium diiodide in THF (Aldrich) in one portion under N₂at room temperature. The reaction was stirred for 1 hour and thenquenched with 250 mL of 1N HCl and stirred for 15 minutes. The reactionwas extracted several times with ethyl acetate and the combined organicextracts were washed with 5% aqueous Na₂ S₂ O₃ solution and thensaturated NaCl solution, dried over Na₂ SO₄ and concentrated. Theresidue was purified on a silica gel column eluting with 40% ethylacetate in hexane to afford 1.53 g of white solid. The NMR spectra wasconsistent for the proposed structure.

EXAMPLE 506 ##STR721##

A 1.5 g quantity of the product from example 505 wasdecarbobenzyloxylated as described in example 489 to yield 1.0 g ofsalt. The NMR spectra was consistent for the proposed structure.

EXAMPLE 507 ##STR722##

To a stirred solution of 2,6-dimethyl-4-cyanopyridine, (3.0 g 22.5 mmol)(JACS, 81, 4004, (1959) in ethanol at 0° C. (12 ml), 30% hydrogenperoxide (9 ml, 87.3 mmol) followed by NaOH (2.16 g, 54 mmol) wereadded. The reaction mixture was stirred at 0° C. for 30 minutes, dilutedwith water (50 ml) and extracted into CHCl₃ (3×50 ml). The organicextracts were separated, dried (Na₂ SO₄) and evaporated to afford thetitle compound (1.7 g, 50%).

EXAMPLE 508 ##STR723##

The compound of example 487 (950 mg)) was hydrogenated in a Parr shakerin EtOH (10 ml)/AcOH (1/2 ml) at 1200 psi and 140° C. over 5% Ru/Ccatalyst for 24 hours. The reaction mixture was filtered, evaporated andthe resulting solid precipitated from diethyl ether/ethanol to affordthe title compound (480 mg) which was used as is in Example 316.

EXAMPLE 509 ##STR724##

To a stirred solution of the compound from Example 507 (800 mg, 5.3mmol) in methanol (35 ml), HCl gas was introduced through a gas inlettube for 35 minutes. The reaction mixture was evaporated in vacuo, toafford the title compound (1.38 g) as a white solid.

EXAMPLE 510 ##STR725##

The title compound was prepared as described in Example 508,substituting the compound of Example 507 with that of 509.

The title compound was used as is in Example 317.

EXAMPLE 511 ##STR726##

To a mixture of acetic anhydride (6 ml) and pyridine (1/2 ml),4-amino-2,6-dimethylpyridine (1.0 g, 8.2 mmol) (Recucil 86, 655, (1967))was added. The reaction mixture was stirred overnight, quenched withaqueous NaHCO₃ and extracted into CHCl₃ (2×50 ml). The organic extractswere dried (Na₂ SO₄) and evaporated to afford an off white solid. Thecrude product was purified by chromatography on silica (eluant, CHCl₃/CH₃ OH/NH₄ OH, 85:14:1) to afford the title compound, (520 mg).

EXAMPLE 512 ##STR727##

The title compound was prepared as described in Example 508,substituting the compound of Example 507 with that of Example 511.

The title compound was used as is in Example 315.

LTA₄ Hydrolase Methods

The following Table presents data demonstrating the pharmacologicalactivity of the LTA₄ hydrolase inhibitors of the present inventionhaving the formula I, Ar¹ --Q--Ar² --Y--R--Z, as defined herein. One ormore of three different assays, (1) an in vitro LTA₄ hydrolase enzymeassay, (2) a human whole blood assay utilizing calcium ionophorestimulation, and (3) a murine ex vivo assay utilizing calcium ionophorestimulation were employed to determine the level of LTA₄ hydrolaseinhibitor activity.

Recombinant Human LTA₄ Hydrolase Assay for LTA₄ Hydrolase InhibitorActivity

Compounds of the present invention were tested for LTA₄ hydrolaseinhibitor activity against recombinant human LTA₄ hydrolase (rhLTA₄ H).Recombinant human LTA₄ hydrolase-encoding vectors were prepared and usedto express rhLTA₄ H essentially as described by J. Gierse, et al.,Protein Expression and Purification, 4, 358-366 (1993). Briefly, LTA₄hydrolase encoding DNA was amplified by polymerase chain reaction usinga pair of oligonucleotide primers based on the nucleotide sequence fromthe 5'-end, and the complement of the 3'-end, of the coding region ofthe LTA₄ hydrolase gene, the nucleotide sequence of which gene is known.(See, C. Funk, et al., Proc. Natl. Acad. Sci. USA 84, 6677-6681 (1987)).A λgt11 human placental cDNA library (Clonetech, Palo Alto, Calif.)provided the nucleic acid template. The LTA₄ hydrolase encoding regionhad a length of about 1.9 kb. The amplified 1.9 kb DNA was isolated andcloned into the genomic baculovirus, Autographa californica nuclearpolyderosis virus (AcNPV) DNA, and the baculovirus expression vector wastransfected into Spodoptera frugiperda Sf-9 cells employing the calciumphosphase co-preciipitation method (see, M. Summers, et al., Tex. Agric.Exp. Stn. Bull. 1555, 1-57 (1987). Recombinant LTA₄ hydrolase enzyme waspurified from the transfected Sf-9 cells essentially as described by J.Gierse, et al., supra.

One or more predetermined amounts of a compound of the invention wereincubated in assay buffer (0.1M potassium phosphate, 5 mg/ml fatty acidfree BSA, 10% DMSO, pH 7.4) for 10 minutes at room temperature with 250ng of recombinant hLTA₄ H to allow binding, if any, between the enzymeand inhibitor. The stock enzyme solution was 1 mg/ml LTA₄ hydrolase, 50mM Tris, pH 8.0, 150 mM NaCl, 2.5 mM beta-mercaptoethanol, 50% glycerol.The specific activity of the enzyme was about 650 nMoles/min/mg. LTA₄(i.e., substrate) was prepared from the methyl ester of LTA₄ (Biomol,Inc., Plymouth Meeting, Pa.) by treating the methyl ester with 30 molarequivalents of LiOH at room temperature for 18 hours. The LTA₄ substratein its free acid form was kept frozen at -80° C. until needed. LTA₄(free acid) was thawed and diluted in assay buffer (minus DMSO) to aconcentration of 350 ng/ml and 25 μl (8 ng) of LTA₄ substrate was addedto the reaction mixture (total volume of reaction mixture=200 μl) attime zero. Each reaction was carried out at room temperature for 10minutes. The reaction was stopped by diluting 25 μl of the reactionmixture with 500 μl of the assay buffer without DMSO. LTB₄ wasquantified in the diluted sample by a commercially availableenzyme-linked immunoassay Caymen Chemical Co., Ann Arbor, Mich.! usingthe method recommended in the manufacturer's instructions and comparedto the amount of LTB₄ produced in a negative control (i.e., essentiallyidentical conditions except without addition of an inhibitor compound).The IC₅₀ was routinely calculated from the data produced.

LTB₄ and Thromboxane Production by Calcium Ionophore Stimulated HumanBlood for LTA₄ Hydrolase Inhibitor Activity

Human blood, collected in heparin-containing Vacutainer tubes, wasdiluted 1:4 with RPMI-1640 media and 200 μl of the diluted blood wasadded into each of the wells of a 96-well microtiter plate. One or moreconcentrations of the leukotriene A₄ hydrolase inhibitor compounds beingtested were prepared (diluted in DMSO) and 2 μl added and gently mixedwith the diluted whole blood. After incubating for 15 minutes at 37° C.in a humidified incubator, calcium ionophore A23187 (Sigma Chemical Co.,St. Louis, Mo.) was added to a final concentration of 20 mcg/ml and theincubation continued under the same conditions for an additional 10minutes to allow LTB₄ formation. The reaction was terminated bycentrifugation (833 g, 10 minutes at 4° C.) and supernatant wereanalyzed for LTB₄ and thromboxane by commercially availableenzyme-linked immunoassays (Caymen Chemical Co., Ann Arbor, Mich.)according to the manufacturer's instructions. The IC₅₀ of each testcompound was determined from the amount of inhibition of LTB₄ productionas compared to an essentially identical assay in which no inhibitorcompound was present.

Ex Vivo LTB₄ and Thromboxane Production by Calcium Ionophore StimulatedMouse Blood for LTA₄ Hydrolase Inhibitor Activity

Leukotriene A₄ hydrolase inhibitor compounds of the present inventionwere diluted to a predetermined concentration in phosphate bufferedsaline containing 2% DMSO and 1% Tween 80. The compounds wereadministered by oral garage to adult male outbred mice weighingapproximately 20-30 gm at a dose of 10 mg/kg body weight. (Compoundsgiven at a dose of 50 mg/kg body weight are designtated in followingTable by the symbol, *.) Sixty (60) minutes after administration of anLTA₄ inhibitor compound of the invention, blood was collected (intoheparin-containing tubes) from the retroorbital sinus. The heparinizedblood was added to the wells of a microtiter plate along with an equalvolume of RPMI-1640 media, and calcium ionophore A23187 was added to afinal concentration of 20 mcg/ml. The mixture was incubated for 10minutes at 37° C. in a humidified incubator. The reaction was terminatedby centrifugation (833 g, 10 minutes at 4° C.). Supernatants wereanalyzed for LTB₄ and thromboxane by commercially availableenzyme-linked immunoassays Caymen Chemical Co., Ann Arbor, Mich.! inaccordance with the manufacturer's instructions. The percent inhibitionwas determined by comparison to animals treated identically except thatthe solution admininstered by oral gavage was devoid of inhibitorcompound.

LTA₄ HYDROLASE INHIBITOR ACTIVITY

    ______________________________________                                                                       Murine Ex Vivo                                                                LTB.sub.4 Inhibition                                            Inhibition of % I LTB.sub.4 /at 1 hour                            Recombinant Calcium Ionophore-                                                                          after                                               Human LTA.sub.4                                                                           Induced LTB.sub.4                                                                           administration of                                   Hydrolase   Production in 10 mg/kg                                            Assay       Human Blood   (* indicates                                   Ex.  IC.sub.50   IC.sub.50     administration of                              #    LTA.sub.4 H HWB           50 mg/kg)                                      ______________________________________                                         44  30 nM       79       nM     25%                                           45  26 nM       116      nM     35%                                           46  1.35 μM  1.5      μM  --                                            48  150 nM      390      nM     --                                            49  190 nM      490      nM     46%                                           62  30 nM       310      nM     --                                            63  40% at 25 μM                                                                           --              --                                            64  52% at 25 μM                                                                           --              --                                            65  110 nM      510      nM     --                                            66  220 nM      220      nM     --                                            67  11 nM       170      nM     0                                             68  480 nM      940      nM     --                                            69  6.52 μM  11.8     μM  --                                            70  35 nM       2.78     μM  --                                            71  6.5 μM   4.26     μM  --                                            76  2.9 μM   3.5      μM  --                                           112  7 nM        82       nM     82%*                                         113  1.23 μM  2.01     μM  --                                           114  3 μM     16       μM  --                                           115  60 nM       190      nM     --                                           116  53 nM       1.09     μM  18%                                          117  3.9 μM   4.15     μM  --                                           118  9 μM     --              --                                           119  4 μM     --              --                                           120  8 μM     --              --                                           121  69 nM       360      nM     48%                                          122  77 nM       219      nM     57%                                          123  7 μM     --              --                                           124  25 μM    --              --                                           125  87 nM       260      nM     46%                                          126  630 nM      1.56     μM  --                                           127  840 nM      2.48     μM  --                                           128  70 nM       890      nM     74%                                          129  16 μM    --              --                                           130  170 nM      1.01     μM  --                                           131  4.3 μM   25       μM  --                                           132  84 nM       500      nM     83%                                          133  10 nM       43       nM     49%                                          134  33 nM       103      nM     63%                                          135  47 nM       91       nM     ?                                            136  77 nM       72       nM     ?                                            137  30 nM       80       nM     38%                                          138  420 nM      520      nM     21%                                          139  110 nM      580      nM     9%                                           140  60 nM       1.01     μM  15%                                          141  13 nM       280      nM     --                                           142  37 nM       100      nM     32%                                          143  56 nM       290      nM     --                                           144  80 nM       900      nM     --                                           147  1.06 μM  730      nM     94%                                          198  30 nM       310      nM     --                                           200  350 nM      1.9      μM  --                                           201  330 nM      1.75     μM  --                                           202  44% at 3 μM                                                                            --              --                                           203  380 nM      3.3      μM  --                                           204  49% at 25 μM                                                                           --              --                                           205  900 nM      1.15     μM  --                                           206  200 nM      1.65     μM  0                                            207  220 nM      640      nM     --                                           208  4 μM     2.15     μM  13%                                          209  3 μM     2.34     μM  0                                            210  4% at 25 μM                                                                            --              --                                           211  120 nM      620      nM     47%*                                         212  3 μM     3.28     μM  --                                           213  1.3 μM   4.65     μM  --                                           214  2.8 μM   10       μM  --                                           215  85 nM       190      nM     33%*                                         225  450 nM      1.86     μM  --                                           226  4% at 100 μM                                                                           --              --                                           227  210 nM      420      nM     23%                                          228  28% at 3 μM              --                                           229  240 nM      220      nM     70%                                          230  390 nM      284      nM     53%                                          231  5 μM     --              --                                           232  2.1 μM   10       μM  --                                           233  370 nM      490      nM     98%                                          234  8 μM     --              --                                           235  10 μM    --              --                                           236  20 μM    --              --                                           237  450 nM      1.86     μM  --                                           238  50 nM       180      nM     49%                                          239  9 μM     --              --                                           240  1.07 μM  2.45     μM  33%                                          241  600 nM      630      nM     33%                                          242  132 nM      608      nM     95%                                          243  70 nM       650      nM     --                                           244  15% at 100 μM                                                                          --              --                                           245  1.77 μM  147      nM     97%                                          246  7 μM     --              --                                           247  100 nM      200      nM     70%                                          248  200 nM      70       nM     56%                                                           605      nM                                                  249  3.2 μM   429      nM     --                                           250  4.9 μM   1.77     μM  --                                           251  330 nM      733      nM     87%                                          252  160 nM      127      nM     94%                                          253  910 nM      490      nM     73%                                          254  6 μM     1.26     μM  87%                                          255  280 nM      608      nM     --                                           256  210 nM      420      nM     23%                                          257  230 nM      1.32     μM  28%*                                         258  1.25 μM  1.44     μM  81%*                                         259  100 nM      440      nM     35%*                                         260  14% at 3 μM                                                                            --              --                                           261  1.25 μM  --              --                                           262  220 nM      2.48     μM  52%                                          263  4.5 μM   8.76     μM  60%                                          264  3 μM     1.10     μM  87%*                                         265  77 nM       450      nM     54%                                          266  6.5 μM   2.64     μM  29%                                          267  170 nM      580      nM     100%*                                        268  53% at 3 μM                                                                            7.98     μM  --                                           269  2.77 μM  1.18     μM  50%                                          270  50 μM    --              --                                           271  11 μM    7.98     μM  --                                           272  7 nM        76       nM     97%                                          273  610 nM      154      nM     100%                                         274  800 nM      1.25     μM  --                                           275  390 nM      146      nM     75%                                          276  4.1 μM   232      nM     75%                                          277  520 nM      546      nM     42%                                          278  22 nM       247      nM     95%                                          279  470 nM      410      nM     57%                                          280  11 nM       21       nM     33%                                          281  93 nM       167      nM     83%                                          282  3.7 μM   1.37     μM  57%                                          283  19 nM       90       nM     90%                                          285  130 nM      1.73     μM  --                                           286  41% at 100 μM                                                                          --              --                                           287  330 nM      2.39     μM  --                                           288  700 nM      960      nM     0                                            289  43 nM       316      nM     --                                           290  450 nM      528      nM     94%                                          291  8 μM     1.85     μM  67%                                          292  7 nM        52       nM     --                                           293  480 nM      3.2      μM  93%                                          294  110 nM      340      nM     57%                                          295  440 nM      604      nM     80%                                          296  710 nM      512      nM     72%                                          297  120 nM      359      nM     63%                                          298  2.5 μM   758      nM     --                                           299  57 nM       133      nM     93%                                          300  5 μM     2.51     μM  --                                           301  4.5 μM   828      nM     81%                                          302  3 μM     2.40     μM  --                                           303  97 nM       1.65     μM  --                                           304  15 nM       112      nM     80%                                          305  10 nM       1.23     μM  42%                                          306  5 nM        177      nM     11%                                          307  440 nM                      --                                           309  2.5 μM   1.77     μM  96%                                          310  930 nM      1.35     μM  96%                                          311  44% at 100 μM                                                                          --              --                                           312  46% at 100 μM                                                                          --              --                                           313  25 μM    --              --                                           314  1.5 μM   --              --                                           315  163 nM      648      nM     53%                                          316  50 nM       131      nM     85%                                          317                                                                           318  2.5 μM   --              --                                                4.2 μM                                                                319  47% at 100 μM                                                         320  14 nM       354      nM     85%                                          321  250 nM      421      nM     87%                                          322  610 nM      154      nM     100%                                         323  800 nM      1.2      μM                                               324  220 nM      586      nM     62%                                          325  20 μM    2.4      μM  --                                           330  900 nM      90       nM     95%                                          331  16 nM       95       nM     97%                                          332  14 μM    --              --                                           333  0.5 μM   --              --                                                1.8 μM                                                                334  1 nM        N5Y             --                                           335  2 nM        115      nM     98%                                          336  31 nM       187      nM     99%                                          337  360 nM      628      nM     82%                                          338  140 nM      690      nM     22%                                          338  8 nM        330      nM     92%*                                         B                                                                             338  34% at 3 μM                                                                            9.15     μM  --                                           C                                                                             339  2.0 μM   13.1     μM  47%                                          340  11 nM       74       nM     61%                                          A                                                                             340  120 nM      330      nM     64%                                          B                                                                             340  550 nM      730      nM     39%                                          C                                                                             341  5.7 μM   8.9      μM  --                                           A                                                                             341  140 nM      930      nM     29%                                          B                                                                             342  970 nM      2.12     μM  --                                           343  40% at 3 μM                                                                            --              --                                           344  ? 11.1 μM                                                                              13.5     μM  --                                           345  35% at 3 μM                                                                            --              --                                           346  31% at 3 μM                                                                            --              --                                           A                                                                             346  1.9 μM   3.57     μM  23%                                          B                                                                             346  2.2 μM   6.69     μM  --                                           C                                                                             347  1.8 μM   7.05     μM  34%                                          A                                                                             347  1.9 μM   5.7      μM  43%                                          B                                                                             347  5 nM        380      nM     52%                                          C                                                                             348  4.6 μM   5.7      μM  42%                                          A                                                                             348  440 nM      560      nM     22%                                          B                                                                             348  290 nM      540      nM     77%                                          C                                                                             349  480 nM      790      nM     78.5%                                        A                                                                             349  300 nM      320      nM     48%                                          B                                                                             349  13 nM       200      nM     52%                                          C                                                                             350  19 μM    13.6     μM  --                                           A                                                                             350  550 nM      950      nM     38%                                          B                                                                             350  620 nM      1.67     μM  35%                                          C                                                                             351  1.08 μM  2.72     μM  --                                           A                                                                             351  290 nM      2.05     μM  71%                                          B                                                                             351  43 nM       360      nM     42%                                          C                                                                             352  120 nM      1.34     μM  29%*                                         353  73 nM       260      nM     0                                            354  51% at 3 μM              --                                           A                                                                             354  280 nM      600      nM     32%                                          B                                                                             354  480 nM      1.18     μM  6%                                           C                                                                             355  1.37 μM  2.23     μM  44%                                          A                                                                             355  870 nM      910      nM     37%                                          B                                                                             355  28 nM       210      nM     48%                                          C                                                                             356  350 nM      1.28     μM  14%                                          A                                                                             356  170 nM      750      nM     33%                                          B                                                                             356  100 nM      340      nM     48%                                          C                                                                             357  47 nM       790      nM     57%                                          A                                                                             357  730 nM      140      nM     60%                                          B                                                                             357  210 nM      420      nM     72%                                          C                                                                             357  40 nM       140      nM     --                                           D                                                                             358  1.55 μM  152      nM     --                                           A                                                                             358  410 nM      640      nM     33%                                          B                                                                             358  87 nM       590      nM     13%                                          C                                                                             359  100 μM   --              --                                           A                                                                             359  10 μM    --              --                                           B                                                                             359  3.5 μM   4.2      μM  --                                           C                                                                             360  36% at 100 μM                                                                          --              --                                           A                                                                             360  19% at 100 μM                                                                          --              --                                           B                                                                             360  5 μM     --              --                                           C                                                                             361  24% at 100 μM                                                                          --              --                                           A                                                                             361  7 μM     --              --                                           B                                                                             362  5.07 μM  3.35     μM  28%                                          A                                                                             362  1.32 μM  4.58     μM  --                                           B                                                                             363  17 nM       57       nM     62%                                          364  36 nM       22       nM     77%                                          365  82 nM       336      nM     72%                                          369  42 μM    1.53     μM  100%                                         370  59 μM    680      nM     96%                                          371  860 nM      650      nM                                                  375  900 nM      240      nM     67%                                          385  140 nM      210      nM     32%                                          386  32 nM       190      nM     51%                                          397  37 nM       120      nM     --                                           398  220 nM      470      nM     0                                            399  100 nM      220      nM     30%                                          400  60 nM       380      nM     --                                           401  55 nM       170      nM     23%                                          402  20 nM       180      nM     58%                                          403  750 nM      3.8      μM  --                                           404  1.75 μM  2.75     μM  52%                                          405  420 nM      2.01     μM  49%                                          406  500 nM      4.0      μM  46%                                          407  20 μM    707      nM     0                                            408  76% at 100 μM                                                                          --              --                                           409  12 μM    --              --                                           410  33 μM    --              --                                           411  2.4 μM   --              --                                           412  190 nM      240      nM     72%                                          413  43 nM       42       nM     86%                                          414  11 μM    830      nM     --                                           415  5 μM     --              --                                           416  410 nM      1.97     μM  31%                                          417  4.3 μM   --              --                                           418  12 μM    --              --                                           419  47 nM       120      nM     90%                                          420  57 nM       133      nM     93%                                          421  410 nM      800      nM     --                                           422  100 nM      660      nM     37%                                          423  330 nM      700      nM     --                                           424  370 nM      850      nM     --                                           425  16 nM       360      nM     60%                                          426  210 nM      403      nM     40%                                          427  350 nM      532      nM     68%                                          428  500 nM      6.6      μM  2%                                           429  250 nM      288      nM     80%                                          430  110 nM      290      nM     37%                                          431  140 nM      280      nM     71%                                          432  140 nM      630      nM     85%                                          433  18 nM       49       nM     71%                                          434  10 nM       63       nM     100%                                         435  225 nM      86       nM                                                  436  720 nM      550      nM     --                                           437  113 nM      693      nM     --                                           438  3.2 μM   --              --                                           439  18 μM    --              --                                           440  30 nM       --              --                                           441  470 nM      410      nM     57%                                          444  300 nM      900      nM     --                                           445  330 nM      367      nM     --                                           446  35 nM       160      nM     70%                                          447  15 nM       292      nM     43%                                          448  820 nM      825      nM     --                                           449  140 nM      913      nM     --                                           450  240 nM      304      nM     91%                                          451  6 nM        ?               90%                                          452  20 nM       290      nM     57%                                          455  11 nM       180      nM     67%                                          456  87 nM       440      nM     72%                                          457  150 nM      620      nM     22%                                          458  560 nM      1.39     μM  --                                           459  1.11 μM  2.4      μM  44%                                          460  84 μM    --              --                                           465  300 nM      470      nM     38%                                          467  60 nM       226      nM     71%                                          496  10 nM       280      nM     54%                                          497  200 nM      216      nM     45%                                          498  56 nM       206      nM     22%                                          499  240 nM      220      nM     60%                                          500  140 nM      142      nM     53%                                          504  29 nM       7.7      μM  --                                           ______________________________________                                         "means Not Determined                                                    

We claim:
 1. A pharmaceutical composition comprising an effective LTB₄-mediated inflammatory disease treating amount of a compound of theFormula I:

    Ar.sup.1 --Q--Ar.sup.2 --Y--R--Z                           (I)

or a pharmaceutically acceptable salt thereof, wherein: Ar¹ is an arylmoiety selected from the group consisting of phenyl, mono-, di-, ortri-substituted phenyl with the substituents selected from the groupconsisting of Cl, Br, F, CF₃, lower alkyl, lower alkoxy, NH₂, NO₂ andOH; Ar² is ##STR728## Q is --O-- or --CH₂ --; Y is --O--; R is selectedfrom the group consisting of:(i) linear or branched C₂ -C₆ alkylenyl; or(ii) --C(R¹⁰)(R¹¹)--(CH₂)m--; and Z is ##STR729## wherein at least oneof R¹ and R² is --(CH₂)_(a) COR¹⁵ and the other is selected from thegroup consisting of:(i) H, (ii) lower alkyl or allyl, (iii) benzyl, (iv)--(CH₂)_(a) COR¹⁵, and (v) --(CH₂)_(a) --OH; R⁷ is H, halogen, loweralkyl, lower alkoxy, nitro, or hydroxy, R⁸ and R⁹ are independently H,halogen, lower alkyl, lower alkoxy, NH₂, NO₂, or OH; R¹⁰ is H, loweralkyl; R¹¹ is H or lower alkyl; R¹⁵ is --OR¹⁶, wherein R¹⁶ is H, loweralkyl or benzyl; a is an integer of from 0 to 5; m is 1, 2 or 3;providedhowever that where either R¹ or R², or both R¹ and R² are --(CH₂)_(a)COR¹⁵, then a is not
 0. 2. A pharmaceutical composition according toclaim 1 wherein R¹ is H or lower alkyl and R² is --(CH₂)_(a) COR¹⁵wherein R¹⁵ is --OR¹⁶.
 3. A pharmaceutical composition according toclaim 2 wherein a is 1, 2 or
 3. 4. A pharmaceutical compositionaccording to claim 3 wherein R¹⁶ is H.
 5. A pharmaceutical compositionaccording to claim 3 wherein R¹⁶ is methyl, ethyl or benzyl.
 6. Apharmaceutical composition according to claim 2 wherein Ar¹ --Q--Ar²--Y-- is ##STR730## wherein Q is --O-- or --CH₂ --, R⁸ and R¹⁹ areindependently H, lower alkyl, lower alkoxy, halogen, NH₂ or NO₂.
 7. Apharmaceutical composition according to claim 2 wherein the compound isselected from the group consisting of:3- 3-4-(phenylmethyl)phenoxy!propyl!amino!propanoic acid; 3- methyl 3-4-(phenylmethyl)phenoxy!propyl!amino!propanoic acid; 3- 4-4-(phenylmethyl)phenoxy!butyl!amino!propanoic acid; 3-3-(4-phenoxyphenoxy)propyl!amino!propanoic acid; 3- methyl3-(4-phenoxyphenoxy)propyl!amino!propanoic acid; 3-4-(4-phenoxyphenoxy)butyl!amino!propanoic acid; and 3- 3- 4-(4-fluorophenyl)methyl!phenoxy!propyl!methylamino!propanoic acid,monohydrochloride.
 8. A pharmaceutical composition according to claim 2wherein the compound is selected from the group consisting of:ethyl 3-3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoate; phenylmethyl 3methyl 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoate; ethyl 3-3-(4-phenoxyphenoxy)propyl!-amino!propanoate; ethyl 3- methyl- 3-4-(phenylmethyl)phenoxy!propyl!amino!propanoate; methyl 3- methyl 3-4-(phenylmethyl)phenoxy!propyl!amino!propanoate, hydrate; ethyl 3- 4-4-(phenylmethyl)phenoxy!butyl!amino!propanoate; phenylmethyl 3- 4-4-(phenylmethyl)phenoxy!butyl!amino!propanoate; phenylmethyl 3-3-(4-phenoxyphenoxy)propyl!amino!propanoate; phenylmethyl 3- methyl3-(4-phenoxyphenoxy)propyl!amino!propanoate; phenylmethyl 3-4-(4-phenoxyphenoxy)butyl!amino!propanoate; methyl 3- 3- 4-(4-fluorophenyl)methyl!phenoxy!propyl!methylamino!propanoate; ethyl 3-4- 4-phenoxyphenoxy!butyl!amino!propanoate; and methyl 3- 3-4-(4-fluorophenoxy)phenoxy!propyl!methylamino!propanoate.
 9. A methodfor treating an LTB₄ -mediated inflammatory disease comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of a compound of the Formula I:

    Ar.sup.1 --Q--Ar.sup.2 --Y--R--Z                           (I)

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein: Ar¹ is an aryl moiety selected from thegroup consisting of phenyl, mono-, di-, or tri-substituted phenyl withthe substituents selected from the group consisting of Cl, Br, F, CF₃,lower alkyl, lower alkoxy, NH₂, NO₂ and OH; Ar² is ##STR731## Q is --O--or --CH₂ --; Y is --O--; R is selected from the group consisting of:(i)linear or branched C₂ -C₆ alkylenyl; or (ii) --C(R¹⁰)(R¹¹)--(CH₂)m--;and Z is ##STR732## wherein at least one of R¹ and R² is --(CH₂)_(a)COR¹⁵ and the other is selected from a group consisting of:(i) H, (ii)lower alkyl or allyl, (iii) benzyl, (iv) --(CH₂)_(a) COR₁₅, and (v)--(CH₂)_(a) --OH, R⁷ is H, halogen, lower alkyl, nitro, or hydroxy, R⁸and R⁹ are independently H, halogen, lower alkyl, lower alkoxy, NH₂,NO₂, or OH; R¹⁰ is H, lower alkyl; R¹¹ is H or lower alkyl; R¹⁵ is--OR¹⁶, wherein R¹⁶ is H, lower alkyl or benzyl;a is an integer of from0 to 5; m is 1, 2 or 3;provided however that where either R¹ or R², orboth R¹ and R² are --(CH₂)_(a) COR¹⁵, then a is not
 0. 10. A methodaccording to claim 9 wherein R¹ is H or lower alkyl and R² is--(CH₂)_(a) COR¹⁵ wherein R¹⁵ is --OR¹⁶.
 11. A method according to claim10 wherein a is 1, 2 or
 3. 12. A method according to claim 10 whereinR¹⁶ is H.
 13. A method according to claim 10 wherein R¹⁶ is methyl,ethyl or benzyl.
 14. A method according to claim 10 wherein Ar¹ --Q--Ar²--Y-- is ##STR733## wherein Q is --O-- or --CH₂ --, R⁸ andR¹⁹ areindependently H, lower alkyl, lower alkoxy, halogen, NH₂ or NO₂.
 15. Amethod according to claim 10 wherein the compound is selected from thegroup consisting of:3- 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoicacid; 3- methyl 3- 4-(phenylmethyl)phenoxy!propyl!amino!propanoic acid;3- 4- 4-(phenylmethyl)phenoxylbutyl!amino!propanoic acid; 3-3-(4-phenoxyphenoxy)propyl!amino!propanoic acid; 3- methyl3-(4-phenoxyphenoxy)propyl!amino!propanoic acid; 3-4-(4-phenoxyphenoxy)butyl!amino!propanoic acid; and 3- 3- 4-(4-fluorophenyl)methyl!phenoxy!propyl!methylamino!propanoic acid,monohydrochloride.
 16. A method according to claim 10 wherein thecompound is selected from the group consisting of:ethyl 3- 3-4-(phenylmethyl)phenoxy!propyl!amino!propanoate; phenylmethyl 3 methyl3-4-(phenylmethyl)phenoxy!propyl!amino!propanoate; ethyl 3-3-(4-phenoxyphenoxy)propyl!amino!propanoate; ethyl 3- methyl-3-4-(phenylmethyl)phenoxy!propyl!amino!propanoate; methyl 3- methyl 3-4-(phenylmethyl)phenoxy!propyl!amino!propanoate, hydrate; ethyl 3- 4-4-(phenylmethyl)phenoxy!-butyl!amino!propanoate; phenylmethyl 3- 4-4-(phenylmethyl)phenoxy!butyl!amino!propanoate; phenylmethyl 3-3-(4-phenoxyphenoxy)propyl!amino!propanoate; phenylmethyl 3- methyl3-(4-phenoxyphenoxy) propyl!amino!propanoate; phenylmethyl 3- 4-(4-phenoxyphenoxy)butyl!amino!propanoate; methyl 3- 3- 4-(4-fluorophenyl)methyl!phenoxy!propyl!methylamino!propanoate; ethyl 3-4- 4-phenoxyphenoxy!butyl!amino!propanoate; and methyl 3- 3- 4-(4-fluorophenoxy)phenoxy!propyl!methylamino!propanoate.